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Review

Talkin’ Toxins: From Coley’s to Modern Cancer Immunotherapy

Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Toxins 2020, 12(4), 241; https://doi.org/10.3390/toxins12040241
Submission received: 11 March 2020 / Revised: 7 April 2020 / Accepted: 7 April 2020 / Published: 9 April 2020
(This article belongs to the Special Issue Toxins and Cancer Therapy)

Abstract

:
The ability of the immune system to precisely target and eliminate aberrant or infected cells has long been studied in the field of infectious diseases. Attempts to define and exploit these potent immunological processes in the fight against cancer has been a longstanding effort dating back over 100 years to when Dr. William Coley purposefully infected cancer patients with a cocktail of heat-killed bacteria to stimulate anti-cancer immune processes. Although the field of cancer immunotherapy has been dotted with skepticism at times, the success of immune checkpoint inhibitors and recent FDA approvals of autologous cell therapies have pivoted immunotherapy to center stage as one of the most promising strategies to treat cancer. This review aims to summarize historic milestones throughout the field of cancer immunotherapy as well as highlight current and promising immunotherapies in development.
Key Contribution: This review summarizes the pivotal milestones in cancer immunotherapy development from Coley’s Toxins to modern day.

1. Introduction

The understanding of immune system governance in neoplastic growth and development has made significant leaps in recent years [1], but its origins can be traced back well over a century ago. Incidence of tumors spontaneously regressing following infectious or pyretic periods have been described throughout history [2,3,4]. However, advancements made in histological diagnosis and assessment of tumor malignancies over the past 100 years have given credence to these claims of immune system modulation in cancer.

2. Pivotal Observations in Cancer Immunotherapy

It is possible that cancer has existed ever since the evolution from unicellular organisms into multicellular entities. However, the oldest record of cancer to date is from a 240 million-year-old fossil containing a shell-less stem turtle, Pappochelys rosinae, with evidence of osteosarcoma [5]. Until recently, the treatment of cancer has historically focused on tumor excision, cytotoxic chemotherapeutic agents, and radiation therapy. Only after the turn of the 21st century did immunotherapy to treat cancer take stage [Figure 1].

2.1. The Story of Coley’s Toxins

William Coley, often regarded as the “Father of Immunotherapy”, was a bone surgeon in New York from 1890–1936 who famously developed a cocktail of heat-killed bacteria, called “Coley’s Toxins”, to treat patients with osteosarcoma. Inspiration for developing this treatment apparently started with one of his first patients, a young woman with osteosarcoma of the hand. Despite his surgical intervention (amputation of the forearm), she succumbed to metastatic disease within months of the operation. This episode had a profound impact on Coley and motivated him to learn more about her disease. He began by reviewing hospital medical records from ninety sarcoma patients, an analysis he later published [6]. While conducting his review, one patient’s course of disease was of particular intrigue. Coley came across the description of a patient with an inoperable sarcoma whose tumor completely regressed after developing erysipelas [7], a type of skin infection [8]. Upon reading this account, Coley wondered if it was possible to induce erysipelas in patients as a means to treat cancer. Fortunately for Coley, a German surgeon named Friedrich Fehleisen had only a few years earlier, in 1883, identified Streptococcus pyogenes as the bacterium responsible for erysipelas [9]. Thus, Coley was able to test his hypothesis and began injecting sarcoma patients with Streptococcus pyogenes, a primitive version of what would later be named Coley’s Toxins.
Over the course of Coley’s career, from 1888–1933, he tested over a dozen different preparations of his toxin. Developing his infamous toxin required striking a balance between safety and efficacy. Indeed, early preparations were highly variable. Some preparations were impotent and failed to produce any signs of infection while other preparations were highly infectious and led to mortality [10]. Eventually, Coley settled on a combination of heat-killed Streptococcus pyogenes and Serratia marcescens [11]. Although Coley was not the first person to make a connection between infection and cancer regression, nor the first to inject bacteria into a patient as a means to mediate tumor rejection, Coley’s efforts were the most comprehensive and influential. In total, it is estimated that Coley himself injected more than 1000 cancer patients and published over 150 papers related to the topic [11].
Coley reported remarkable success with his toxins and published many reports of his toxins inducing tumor regression [12,13]. However, at the time, his findings were highly controversial and were met with harsh criticism by many of his colleagues. Notable critiques include those in the Journal of the American Medical Association in 1894 issuing a statement criticizing the use of his toxins as well as the FDA re-categorizing of “Coley’s Toxins” in 1963 as an investigational drug that lacked safety and efficacy data, despite over 70 years of use and numerous publications [11]. This recategorization made it illegal to prescribe Coley’s Toxins outside of clinical trial testing. In the end, history would be on the side of William Coley. Years after his death, his toxins were re-evaluated in a controlled trial and were demonstrated to mediate antitumor effects [14]. Moreover, advancements in fundamental understanding of cancer and the immune system have allowed his findings to become more widely accepted and to lay a foundation for future studies of cancer immunotherapy.

2.2. Evidence the Immune System Targets Cancer

Although Coley never fully understood the mechanism by which his toxins functioned, he gathered substantial evidence linking the immune system and cancer. Further clarity and development of this connection would come years later in the form of the immunosurveillance hypothesis. The idea that the immune system possesses a capacity to recognize and eliminate cancer cells was first postulated by Paul Ehrlich in 1909 [15]. While direct experimental evidence during this time period was lacking, Ehrlich reasoned that the incidence of cancer is relatively low but that the formation of aberrant cells is a common phenomenon, suggesting the existence of a host defense system against cancer. Over 50 years later, these ideas were further developed by Burnet and Thomas and formally coined the “immune surveillance” hypothesis [16,17].
Early experimental evidence for the existence of tumor-specific immunity derives from transplantation studies. In 1943, Luwik Gross utilized methylcholanthrene (MCA) to chemically induce sarcoma in a C3H mouse and then transplanted this sarcoma into syngeneic mice. While inoculation with high doses of tumor cells often killed mice, Gross found that inoculation with low doses of tumor cells led to a period of growth followed by gradual tumor regression. In these surviving mice, tumor challenge using high doses of tumor cells invariably led to rejection, suggesting these animals developed immunity to the tumor [18]. Further support for immunosurveillance comes from a seminal study by Prehn and Main in 1953. In these studies, an array of sarcomas from multiple syngeneic mice were generated using MCA. Prehn and Main found that inoculation of a mouse with sarcoma from one source protected that mouse from future challenge using the same sarcoma source but did not protect against challenge using sarcoma derived from a different mouse [19]. Moreover, Prehn and Main demonstrated that transplantation of skin tissue from a donor mouse did not sensitize the recipient mouse to the donor’s sarcoma, directly addressing a common critique at the time that rejection was mediated by subtle differences in genetic backgrounds. Collectively, these studies further supported the existence of tumor-specific immunity, adding the nuance that tumor antigens are highly unique to a tumor even in tumors of the same histological type, induced by the same chemical means, and from mice of the same genetic background [19].
While studies in partially immunocompromised mouse models over the following decades failed to support the immunosurveillance hypothesis, definitive demonstration of immunosurveillance came in the early 2000s following a series of studies conducted in novel, specifically immunocompromised, mouse strains. In 2001, Robert Schreiber’s group compared the incidence of spontaneous neoplasms between wild-type and Rag2−/− mice (Rag2 encodes a protein necessary for somatic recombination and thus Rag2−/− mice lack mature T and B lymphocytes) [20]. In mice over 15 months old, fewer than 20% of wild-type mice contained neoplastic disease while 100% of surveyed Rag2−/− mice developed spontaneous neoplastic lesions in various tissues, suggesting functional T and B lymphocytes suppress the development of cancer. Moreover, the same study observed that Rag2−/− mice, as well as Ifngr1−/− and Stat1−/− mice, which are deficient in vital immune signaling pathways, develop higher incidences of sarcoma compared to wild-type mice in MCA-induced tumor models [21]. Similarly, higher incidences of MCA-induced tumors were reported by additional investigators using mice deficient in other vital immune-signaling molecules such as perforin or TNF-related apoptosis-inducing ligand (TRAIL) [22,23]. These experimental studies in mice are mirrored by clinical evidence that humans with compromised immune systems develop higher incidences of cancer. Indeed, individuals born with genetic defects in immune-related genes develop higher incidences of lymphoma [24]. Moreover, people with otherwise normal immune function who acquire AIDS infection or transplant patients who receive immunosuppressive drugs are both at higher risk for developing Non-Hodgkin’s lymphoma and virus-induced Kaposi Sarcoma [25,26].
Since the emergence of the immunosurveillance hypothesis, the interplay between the immune system and cancer has been further refined and renamed as the process of “immunoediting” [27]. Immunoediting posits that the immune system and cancer intersect at three stages: elimination, equilibrium, and escape. During the elimination stage, the immune system recognizes and destroys many, but not all aberrant cells. During equilibrium, the immune system and the tumor exert opposing forces, effectively resulting in containment of the tumor. Over time, as the cancer acquires additional mutations and as the immune system exerts a selective pressure eliminating immunogenic cells and leaving behind non-immunogenic cells, the cancer eventually fully escapes immune surveillance. In this final escape stage, the cancer has fully circumvented detection by the immune system and undergoes rapid and uncontrolled growth. Evidence for equilibrium and escape stages is supported by experiments in mice with stagnant tumor sizes who then undergo rapid growth after immune cell depletion [28]. Additionally, tumors arising from immunocompromised mice are more frequently rejected when transplanted into a wild-type host compared to tumors arising from immunocompetent mice [21], partly reflecting immune-induced antigen loss in the presence of an intact immune system [29] (immunoediting). Thus, the fundamental goal of cancer immunotherapy is to overcome the years to decades of immunoediting to generate antitumor immunity that is sufficient to completely eliminate the patient’s cancer and cure their disease.

3. Immunomodulatory Agents

Immunomodulators comprise a variety of therapeutic agents and treatment strategies that aid in normalizing, or in the context of cancer, re-engaging or boosting immune cell function to counter uncontrolled cell proliferation. By definition, a tumor that presents in the clinic can be said to have escaped normal immune control, even if tumor-reactive T cells are detected in the blood or have infiltrated the tumor tissue [30]. Although tumor cells themselves possess intrinsic immunosuppressive behaviors, such as cultivating a hypoxic microenvironment [31,32] or generating lactic acid [33], the majority of suppressive influence comes from the normal functions of suppressive immune cells, cytokines, and inhibitory surface molecules [34,35]. Under normal physiological circumstances, these mechanisms suppress T-cell priming and cytotoxic T-cell function to stave off unwarranted autoinflammatory responses [36]. Therefore, many of the immunomodulatory agents described herein aim to directly oppose these immunosuppressive mechanisms and to re-engage the immune system.

3.1. Cytokine Therapy

Prior to understanding their therapeutic immunomodulatory potential in cancer, cytokines were first recognized as systemic soluble factors that could regulate lymphocyte function and inflammatory responses. In 1972, a group from Yale University School of Medicine first characterized a “lymphocyte activating factor” that spurred lymphocyte proliferation in response to soluble agents released by other syngeneic immune cells [37]. These agents were partially purified from antigen-stimulated, lymphocyte-conditioned media and characterized further as “T-cell growth factor” that could support cytotoxic T cells capable of killing autologous leukemic myeloblasts [38]. Shortly thereafter, this key growth factor was definitively purified and described as interleukin-2 (IL-2) [39], which not only allowed T lymphocytes to be cultured in large quantities ex vivo, but also allowed recombinant IL-2 to be administered as a high-dose single-agent [40], or used in tandem with preconditioned and transplanted cancer-specific lymphoid cells [41,42]. A comprehensive report published in 1987 by the NCI’s Surgery Branch documented objective responses to high-dose IL-2 and regression of tumors in patients with metastatic melanoma and renal cell cancer [43]. Adjustments made to IL-2 dose scheduling would largely combat acute toxicities, the most prominent being capillary leak syndrome and hypovolemia [44]. These results and safety measures would spur numerous and larger cohort studies utilizing IL-2 in a metastatic setting [45,46], culminating with FDA approval of high-dose intravenous IL-2 for patients with metastatic renal cancer in 1992, and metastatic melanoma several years later. This would be noted as one of the first FDA-approved cancer immunotherapies [47].
Other cytokines that have demonstrated translational applications include interleukin-15 (IL-15), interferon-alpha (IFNα), and granulocyte macrophage colony-stimulating factor (GM-CSF). While both structurally similar and capable of stimulating early T-cell proliferation and NK cell engagement much like IL-2, IL-15 additionally supports memory CD8+ T-cell persistence, a known mediator of long-term antitumor immunity [48]. IL-15 has also proven to be an effective mediator of antitumor protection in murine models of cancer [49,50,51,52]. In support of these claims, phase 1 clinical trials utilizing recombinant IL-15 alone, and in conjunction with B-cell-depleting antibodies, are currently underway for treating both solid and liquid tumors, respectively [NCT01021059, NCT03759184].
IFNα, another cytokine originally described in the context of mediating antiviral immune response [53,54], was also identified to inhibit tumor neovasculature, upregulate MHC class I expression, mediate dendritic cell maturation, activate B and T cells, and induce apoptosis—all favorable antitumor attributes [55]. Thanks to the efforts of blood banking that began in the late 1970s [56], adequate quantities of purified IFNα spurred a burst of clinical evaluations in patients with hematological malignancies [57,58] and solid tumors, such as renal cell cancers and malignant melanoma [59,60]. These trials culminated in FDA approval of IFNα as an adjuvant therapy first in rare forms of leukemia, and later in patients with high-risk stage II and stage III melanoma [61].
As the name suggests, GM-CSF was originally identified as a regulator of granulocyte and macrophage differentiation, as well as general hematopoiesis of multi-lineage progenitors [62]. However, in 1993, Dranoff and colleagues transduced B16 melanoma cells with ten known pro-inflammatory mediators, vaccinated mice with these constructs, and then challenged them with live B16 cells. Of the ten, GM-CSF conferred the largest magnitude of antitumor immunity [63]. These findings prompted strategies to deliver GM-CSF to patients, either by vaccinating patients with irradiated tumor cells engineered to secrete the cytokine [64], or by single-agent dosing [65]. Although the exploration of GM-CSF-expressing tumor vaccines has waned in recent years due to limited clinical efficacy [66], combination strategies employing recombinant GM-CSF with other immunomodulatory agents, such as checkpoint inhibitors [67] and additional cytokines [68] have enhanced overall survival in melanoma patient trials.

3.2. Immune Checkpoint Inhibitors

Suppression of immune cell activation, infiltration, and effector functions required for tumor cell clearance can be largely attributed to the immunosuppressive conditions within the tumor microenvironment [69]. In several studies, “dysfunctional” CD8+ T cells were retrieved from patient tumors and nearby draining lymph nodes and said to be lacking the expected differentiation profiles [70], or impaired by the accumulation of repressive Foxp3+ regulatory T cells (Tregs) [71]. A similar phenomenon was originally described in mice infected with a lymphocytic choriomeningitis virus, whereby chronic antigen stimulation induced an “exhausted” T-cell state proceeded by T-cell receptor (TCR) downregulation [72]. The discovery of other requisite activating co-stimulatory signals in addition to canonical antigen stimulation with the TCR [73], which was now known to be insufficient for fully functional T-cell activation [74], gave clues to the complex nature of balancing activation with self-antigen tolerance [75]. Immune homeostasis is dependent upon these co-stimulatory/co-inhibitory receptor-ligand interactions, which in the correct context, safeguard against chronic immune activation and excessive inflammatory responses [76]. Addressing these phenomena directly, immune checkpoint blockade selectively restricts these co-inhibitory signaling mechanisms that have been co-opted by cancer cells, thereby enhancing antitumor T-cell activity.
Although initially identified in 1987 [77], the 1994 discovery of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) co-inhibitory receptor pairing with the B7 co-stimulatory ligand is perhaps the most substantial [78]. Upregulation of CTLA-4 on both CD4+ and CD8+ T lymphocytes was identified as a negative regulator of T-cell activation and effector functions [79,80], while murine models deficient in CTLA-4 experienced massive lymphoproliferation and tissue infiltration due to over-activation of resident T cells [81,82]. In the late 1990s, Dr. James Allison’s group at University of California, administered an inhibitory antibody to block the CTLA-4 co-inhibitory synapse in mice burdened with tumors. Both orthotopic and pre-established tumor cells were rejected following administration of the anti-CTLA-4 antibody, indicating that blockade of inhibitory signals associated with the co-stimulatory pathway can enhance antitumor immunity [83]. These indications prompted the application of CTLA-4 blockade in patients with stage III/IV unresectable melanoma with remarkable success [84], culminating in the 2011 FDA approval of the anti-CTLA-4 monoclonal antibody (mAb), ipilimumab, as an adjuvant therapy for patients with cutaneous melanoma. Retrospective studies have revealed marked increases in survival benefit compared to traditional chemotherapy regimens [85,86], with modest gains observed in other solid tumor types currently in various phases of clinical trials [87].
In an effort to identify genes associated with apoptosis, Dr. Tasuku Honjo’s group at Kyoto University discovered programmed cell death protein 1 (PD-1), a lymphoid cell surface protein that the group hypothesized to be a cell-death inducer [88]. Several years later in 1999, the same group generated a PD-1 deficient mouse model that spontaneously developed several autoimmune-like symptoms and systemic graft-versus-host-like disease [89]. Like CTLA-4, PD-1 was identified as a negative regulator of adaptive immune responses. PD-1 ligand 1 (PD-L1) was discovered that same year at the Mayo Clinic and characterized as functionally homologous to the CTLA-4 ligand, B7, but co-stimulated T cells through some additional unknown receptor [90], later identified to be PD-1 [91]. Engagement of PD-1 with its ligand prevented T-cell proliferation and cytokine production when synthetically stimulated, identifying it as an intrinsic inhibitory mechanism of autoreactive lymphocyte activation [91]. PD-L1 surface expression on tumor cells was also discovered to suppress the cytolytic effector functions of CD8+ T cells, with additional speculation that PD-1/PD-L1 blockade could serve as an effective strategy to combat tumor cell escape [92]. Speculation became reality when several groups tested PD-L1 blockade in murine tumor models and concluded that antibodies directed at this co-stimulatory interaction could enhance cancer immunotherapy [93,94,95]. In one step closer to the clinic, PD-L1 was determined to be a prognostic marker of patient outcome, with higher levels of ligand in resected specimens correlated with poorer patient survival [96]. Within the past 10 years, several high-profile trials employing anti-PD-1/PD-L1 mAbs under various conditions, dosing strategies, and cancer types, have indicated that blockade of this co-inhibitory pathway is both well-tolerated and associated with durable objective responses in patients [97,98,99]. Consequently, FDA approval was granted first to nivolumab, a humanized PD-1 mAb for metastatic melanoma in 2014, and subsequently for pembrolizumab, a PD-1 mAb alternative. Both therapies elicited greater overall patient survival compared to their anti-CTLA-4 counterpart [100,101]. In 2016, a third antibody was developed, this time directed at the PD-L1 ligand to treat patients with urothelial carcinoma and non-small cell lung cancer with much success [102,103]. This fully humanized anti-PD-L1 mAb, atezolizumab, was granted FDA approval for bladder cancer patients ineligible for traditional cisplatin-based chemotherapies [104]. Recent studies have expanded the number of indications for anti-PD-1/PD-L1 blockade alone [105], and in combination with anti-CTLA-4 [106], both proving to be summarily efficacious.
Although CTLA-4 and PD-1 blockade strategies have demonstrated unprecedented clinical success and accelerated FDA approval, there remains a population of non-responders. These individuals either fail to respond to checkpoint blockade from treatment onset due to innate resistance mechanisms, or acquire secondary resistance resulting in relapse. Retrospective studies of large-cohort clinical trials may expose novel biomarkers capable of predicting resistance to checkpoint therapies [107]. Additional co-inhibitory receptors, each with unique functions, have since been identified to influence negative immune regulation by various mechanisms [108]. Likewise, recent findings have demonstrated that the resident gut microbiome has the ability to influence patient responses to checkpoint blockade, with individuals who had consumed oral antibiotics prior to therapy experiencing poorer anti-PD-1 responses [109,110]. Nonetheless, immune checkpoint inhibitors continue to represent the vast majority of new immunotherapies for the treatment of cancer. These therapies would not be possible without seminal discoveries made in the blockade of negative immune regulatory elements by Drs. James Allison and Tasuku Honjo, for which they were awarded the 2018 Nobel Prize in Physiology or Medicine.

4. Vaccines

While immunomodulatory agents broadly stimulate the immune system, cancer vaccines aim to more precisely steer an immune response towards cancer. At its purest form, a cancer vaccine consists of one or more tumor antigens combined with an adjuvant to enhance the immune response. As will later be described, the type of tumor antigen, delivery method of the antigen, and adjuvant varies greatly. Cancer vaccines can be administered as a therapeutic vaccine in patients with existing malignancies or as a preventive vaccine in healthy or high-risk individuals (primary prevention) or patients in remission (secondary prevention) to protect against future tumor development or recurrence, respectively.

4.1. Tumor Antigens

Initial attempts at vaccination occurred before the identification of specific tumor antigens. These trials utilized cellular-based vaccines consisting of modified or irradiated tumor cells derived from a patient (autologous) or from a cancer cell line (allogeneic) injected with adjuvant [111,112,113]. With the identification of the first human tumor antigen, MAGE-1, by Thierry Boon’s group in 1991, a more refined approach of vaccinating against specific targets was born [114]. Since then, over 75 tumor-associated antigens have been identified [115]. There are two categories of tumor antigens: tumor-associated antigens and tumor-specific antigens. By definition, tumor-associated antigens share expression with some normal tissues while tumor-specific antigens are unique to cancer cells. Notable examples of tumor-associated antigens that have been a focus of multiple immunotherapies include the cancer-testis antigens NY-ESO-1 [116] and MAGE-1 [117], which are expressed by germ cells and ectopically re-expressed in cancers; the oncofetal antigens CEA [118] and alpha-1-fetoprotein [119], which are present during fetal development and re-expressed by cancers; differentiation antigens, such as prostate-specific antigen (PSA) [120] and CD19 [121], which are expressed by cells derived from a specific tissue-type and retained in cancers; and antigens that are over-expressed by cancers relative to normal tissue, including HER2 [122] and telomerase [123]. In contrast to tumor-associated antigens, which share expression with healthy tissue, tumor-specific antigens are exclusively expressed by tumors. Tumor-specific antigens, also known as neoantigens, are mutated peptides created by unique genetic aberrations or may be viral antigens in the case of virus-associated cancers [124].

4.2. Therapeutic Cancer Vaccines

In 1995 and 1996, the first clinical trials testing cancer vaccines against tumor-associated antigens were published. These trials utilized either peptide vaccines [125], or peptide-pulsed dendritic-cell vaccines composed of patient-derived dendritic cells that have been incubated with a peptide prior to re-infusion [126,127]. Other popular methods of cancer vaccination include the use of recombinant viral and bacterial vectors. As microorganisms potently stimulate the immune system, the use of these vectors to deliver tumor antigen in the context of an infection is hypothesized to enhance antitumor immune responses. Common vectors used to deliver tumor antigens include poxvirus [128], adenovirus [129], Salmonella typhimurium [130], and Listeria monocytogenes [131]. As methods of gene therapy have advanced over the years, the use of DNA and RNA vaccines has become increasingly common [132].
Despite thousands of cancer vaccine clinical trials, only one therapeutic cancer vaccine, Sipuleucel-T, is FDA-approved [133]. Sipuleucel-T is an autologous cell vaccine composed of patient peripheral blood mononuclear cells (PBMCs) pulsed with a chimeric protein consisting of the tumor-associated antigen prostate alkaline phosphatase (PAP) fused to the immunomodulating cytokine GM-CSF. A phase III clinical trial in men with metastatic castration-resistant prostate cancer found that three infusions of Sipuleucel-T led to the induction of PAP-specific immune responses and a 4.1-month improvement in median survival [134].
Limited success in therapeutic settings may be, in part, attributed to poor immunogenicity of the vaccine target and immunosuppressive tumor microenvironments. One approach to overcome poorly immunogenic tumor-associated antigens is the recent trend towards targeting neoantigens. Compared to tumor-associated antigens, neoantigens may be more immunogenic due to a lack of immunological tolerance mechanisms [135]. Until recently, the identification of neoantigens was impractical as the cost and time to sequence patient genomes for unique mutations presented a formidable barrier. However, with advancements in next-generation sequencing, it has become feasible to sequence a patient’s normal and tumor genome to identify unique tumor-specific antigens. Personalized therapeutic neoantigen vaccines have shown promise in phase I trials for melanoma [136] and glioblastoma [137]. However, these neoantigen vaccines are in early clinical testing, and thus the efficacy and feasibility of this approach is yet to be determined.

4.3. Preventive Cancer Vaccines

Recently, there has been a trend towards testing cancer vaccines as preventive therapies. Vaccination in preventive settings may be preferable to therapeutic ones as it may allow for the induction of antitumor immunity before the development of immunosuppressive microenvironments [138]. This strategy has shown promise against multiple viral-based cancers. Indeed, vaccination against oncogenic viruses including hepatitis B and human papillomavirus have led to reductions in hepatic [139] and cervical [140] cancers, respectively. However, for non-virally associated cancers, a target antigen and clinical setting to administer preventive vaccines is often less clear. For example, vaccinating a healthy patient against a tumor-associated antigen may carry an unnecessary risk of autoimmunity. Additionally, preventive vaccination against neoantigens, while reducing the risk of autoimmunity, may be impractical as neoantigens are often widely variable between patients. However, preventive vaccination in some settings may be possible. One such example is vaccination against the mucin 1 (MUC1) antigen in patients at high-risk of colorectal cancer. In tumors, MUC1 is hypoglycosylated relative to normal tissues, allowing for the induction of selective antitumor responses [141]. A phase I/II study in patients with a history of colorectal adenoma demonstrated MUC1 immunogenicity and a phase II trial investigating the ability of MUC1 vaccine to prevent adenoma recurrence is currently ongoing [142].

4.4. Oncolytic Virotherapy

An emerging immunotherapeutic strategy that is often categorized as a cancer vaccine is the use of oncolytic viruses. Oncolytic viruses preferentially infect and kill tumor cells compared to normal tissue. Selective infection of tumor cells is achieved through a combination of factors including the overexpression of viral receptors on tumor cells which can facilitate viral entry, a proliferative cell cycle that promotes viral replication, and a tumor cell deficiency in type I interferon production leading to limited viral clearance [143]. In addition to mediating tumor regression by direct cell lysis, viral infection activates components of the innate and adaptive immune system, thereby contributing further to tumor cell death. For example, oncolytic viral infection activates NK cells to clear virally-infected tumor cells [144]. Moreover, immunogenic cell death of virally infected tumor cells releases both tumor-associated antigens and neoantigens that can be acquired and presented by antigen-presenting cells, leading to the induction of antitumor CD8+ T cell responses (an approach often described as “in situ vaccination”) [145,146].
The potential of oncolytic virotherapy was first noted by George Dock in 1904. Similar to Coley, Dock noticed that a patient with acute leukemia underwent remission after acquiring an influenza infection [147]. Many other case reports followed over the years, eventually leading to hundreds of clinical trials testing oncolytic viruses [148]. In 2015, the first oncolytic viral therapy, talimogene laherparepvec (“T-VEC”), was approved by the FDA for use in metastatic melanoma [143,149]. T-VEC is an attenuated herpes simplex virus harboring various genetic deletions and insertions designed to enhance the antitumor immune response, such as the deletion of an immune-evasive viral gene ICP47 and the insertion of a human GM-CSF gene [145]. Compared to GM-CSF administration alone, T-VEC led to a 4.4 month increase in median survival in a phase III trial in patients with advanced and metastatic melanoma [143,149].

5. Adoptive Cell Therapy

5.1. Tumor-Infiltrating Lymphocytes and Engineered T-Cell Receptors

The antitumor activity of T lymphocytes was first elucidated in the 1950s and 1960s with seminal discoveries made in allograft rejection of sarcomas in experimental rodent models [150,151]. In 1953, Mitchison investigated the passive transfer of tumor immunity via transplantation of lymph nodes from mice inoculated with lymphosarcomas to equivalently challenged, but non-inoculated, mice [152]. A decade later, two groups made similar observations of transferrable tumor immunity by isolating and transplanting the cells of lymphatic tissues, rather than the organs themselves. Cells were collected from the lymphatic ducts and spleens of donor animals previously immunized with sarcoma cells that developed palpable tumors. Administration of those lymphoid cells back into syngeneic and non-syngeneic recipients inoculated with tumors, saw sustained regression indicating that these lymphocytes were “educated” by prior exposure to tumor antigens [153,154].
The means to exploit these T lymphocytes for their antitumor potential was limited by the inherent difficulty of expanding cells ex vivo. In 1976, a group at the NIH first described the co-culture of isolated human bone marrow with conditioned media containing IL-2 that could induce growth and differentiation of bone marrow cells to T lymphocyte precursors [155]. With the advent of commercially synthesized IL-2, T lymphocytes could now be cultured in large quantities, or in the context of an adjuvant, to boost the therapeutic effects of tumor-sensitized and adoptively transferred T lymphocytes [156]. This subset of cytokine-activated lymphocytes was identified to be among those infiltrating the stroma of transplanted tumors. Dr. Steven Rosenberg’s group confirmed that tumor-infiltrating lymphocytes (TILs) isolated from resected tumor could recognize syngeneic tumor cells in vitro [157], as well as mediate durable antitumor responses when re-administered back into autologous animal models [158] and cancer patients with metastatic disease [159].
The relatively pure populations of CD8+ and CD4+ T cells cultured from resected tumors appeared to dissipate quickly when returned to patients, meaning that therapeutic responses were often transient. However, in 2002, prior application of a lymphodepleting, nonmyeloablative chemotherapy regimen, originally designed for allogeneic bone marrow transplantation [160], greatly enhanced TIL engraftment and clonal persistence in patients, with some individuals harboring up to 80% CD8+ T cells many months post-infusion [161,162]. Shortly thereafter, another milestone was achieved when the Rosenberg group retrovirally transduced patient-derived peripheral blood lymphocytes with a TCR recognizing the common melanoma antigen, MART-1. Objective cancer regression was observed in 2 out of 15 patients (13%) when engineered T lymphocytes were adoptively transferred back into patients [163], with a subsequent report demonstrating an improved 30% objective response rate [164]. Additional trials employing engineered TCRs targeting NY-ESO-1 in synovial cell sarcoma [165], the GD2 disialoganglioside in neuroblastoma [166], and carcinoembryonic antigen (CEA) in colorectal cancer [167] demonstrated objective clinical responses, thereby broadening the application to additional tumor types. More recently, personalized strategies using whole-exome sequencing of patient tumors has given researchers the ability to target neoantigens with high specificity [168,169]. Classically unmanipulated TIL therapy will continue to serve a patient population with shared and broadly targetable antigens [170], while more nuanced TILs recognizing neoantigens will continue to pace evolving therapies in the age of personalized medicine [171].

5.2. Chimeric Antigen Receptor T Cell (CAR-T Cell) Therapy

Although adoptive transfer of tumor-sensitized and antigen-reactive TILs with prefatory lymphodepletion and IL-2 dosing regimens had proven effective in the clinic, patient responses were often transient: shrinkage in metastatic lesions could occur, without objective response to treatment [172]. Native TCRs are often limited by their ability to recognize post-translationally or aberrantly modified proteins, such as those observed in tumor-associated antigens of malignant cells [173,174]. Likewise, T cells dependent on antigen presentation by MHC molecules are routinely hindered by MHC class I downregulation, a selective mechanism of tumor immune escape [175].
In 1989, an Israeli group at the Weizmann Institute of Science devised the first proof-of-concept strategy using an engineered chimeric antigen receptor (CAR) to circumvent the need for MHC-mediated antigen presentation for T-cell activation. By combining the intracellular T-cell receptor circuitry with the antigen-recognizing variable domains of an antibody raised against 2,4,6-trinitrophenyl (TNP), the researchers were able to elicit a non-MHC-restricted response in transfected T lymphocytes to target cells bearing TNP on their surface [176]. The unprecedented antibody-type specificity, now liberated from MHC presentation and paired to effector T-cell function, could conceivably target post-translationally modified proteins characteristic of tumor cells undergoing selection or escape. Several years later, the same group successfully generated CARs directed towards HER2, a cell surface antigen commonly overexpressed in adenocarcinomas. These CAR-T cells selectively lysed HER2+ cancer cells in vitro, providing evidence that mAbs directed towards common tumor cell antigens, could be reassembled into single chain variable fragments (scFvs) to facilitate immune effector function directly [177]. That same year, a joint venture between Weizmann Institute and the NIH expanded the spectrum of available targets by targeting folate receptors commonly overexpressed in ovarian carcinoma cells and further demonstrating the potential of adoptively transferring these CAR-T cells into cancer patients [178].
In an effort to improve CAR-T cell activation, CD28 costimulatory molecules were added in a single tandem gene product with the intracellular CD3ζ-chain. Tumor cells often lack costimulatory molecules entirely, a barrier to persistent activation in first-generation CAR-T cells. Much like conventional T cells, an “exhausted” phenotype was observed in T cells expressing first-generation constructs encountering tumor cells in excess. In contrast, second-generation CAR-T cells containing additional built-in CD28 costimulatory moieties demonstrated superior signaling functionality, persistence, and cytokine production [179,180], as well as antitumor activity [181]. Over the next decade, second-generation CARs would be the basis for many first-in-human studies: first targeting carbonic anhydrase IX (CAIX), an antigen commonly overexpressed in renal cell carcinoma (RCC), and shortly thereafter, the ovarian cancer–associated antigen α-folate receptor (FR). CAIX-directed CAR-T cells produced grade 2–4 liver toxicity in patients due to CAIX self-antigen present in normal bile duct epithelium, with no overall response in RCC tumors [182]. Likewise, FR-directed CAR-T cells in a parallel phase 1 study, produced no reduction in ovarian tumor burden, albeit with lower grade 1–2 toxicity and no detectable off-tumor or off-target responses [183].
Major clinical breakthroughs were not seen until several years later when CAR-T cell therapy strategy switched from targeting primarily solid tumors, to liquid tumors, such as B-cell lymphomas and leukemias. In 2008, a group at University of Washington pioneered a proof-of-concept clinical trial in which refractory B-cell lymphoma patients received 20 infusions of autologous CD20-directed CAR-T cells. Treatment was well-tolerated in patients, with minimal toxicities and modified T cells persisting up to 9 weeks. Of the seven patients, two were noted as having complete response to treatment [184]. With phase 1 clinical trials rapidly taking shape around B-cell targets, methods for manufacturing and validating clinical-grade autologous CAR-T cells were developed to support increasing demand [185]. Shortly thereafter, the Rosenberg group within the NCI’s Surgery Branch, demonstrated in vivo antigen-specific activity of CAR-T cells directed towards the B-cell-specific antigen, CD19, in advanced-stage follicular lymphoma [186]. Paralleling this seminal study, Dr. Carl June’s group at the University of Pennsylvania demonstrated specific and effective on-target killing of CD19+ malignant B cells in patients with advanced chronic lymphocytic leukemia (CLL) using CD19-directed CAR-T cells. In that study, two out of three patients experienced complete remission of disease, with a portion of CAR-T cells retaining potent effector function six months after initial infusion, indicating a possible memory CAR-T cell phenotype [187,188]. The CAR employed by the University of Pennsylvania possessed a 4-1BB (CD137) costimulatory domain, rather than CD28, that promoted in vivo persistence and antileukemic function that outperformed conventional CARs with either CD3ζ and CD28 costimulatory molecules or CD3ζ alone [187,189].
Over the next few years, both groups continued to advance the field by targeting various CD19+ hematological malignancies with great success. However, unanticipated and oftentimes severe neurological toxicities in the form of cytokine release syndrome were observed in patients. This toxicity can manifest as fevers, headaches, aphasia, and in some cases, hallucinations, delirium, and seizures [190]. Cytokine blockade strategies to control the abundance of systemically released cytokines, namely administering the IL-6-blocking antibody tocilizumab with and without corticosteroids, were developed to combat acute neural toxicity [191,192,193,194,195]. Although major clinical gains have been achieved with CD19+ hematologic malignancies, the same successes have yet to be fully realized in solid tumors. Despite abundant antigenic heterogeneity, difficulties in trafficking to tumor sites, and an intrinsic immunosuppressive tumor microenvironment [196,197], CAR-T cell therapies against solid tumor malignancies have entered early-phase clinical trials with varying degrees of success [Table 1].

6. Conclusions

The late 19th century observation that tumors could be treated with cocktails of heat-killed bacteria has proven highly influential. Unbeknownst to William Coley and his contemporaries, this would prove to be one of the first documented cases of tumor regression by induced activation of the immune system. Coley’s legacy would help spur subsequent hypotheses of immunosurveillance mechanisms capable of mediating steady-state tumor recognition and elimination. Over the next century, exploitation of these mechanisms was to become a major priority as immunotherapies continued to evolve.
Treatment regimens using recombinant cytokines that activate immune cell proliferation and effector functions are efficacious in treating selected patient populations. Likewise, strategies employing immune checkpoint blockade against tumor cells that express co-inhibitory molecules have reached clinical milestones once thought to be unachievable. Vaccines against tumor-associated antigens have demonstrated clinical benefit, with applications turning towards neoantigens as patient-specific tumor sequencing becomes feasible. FDA approval of the oncolytic virotherapy, T-VEC, may also offer another option for locally-acting immune stimulation and antitumor activity when resection, chemotherapy, or radiation are not amenable. Moreover, the success of CAR-T cell therapy in patients with hematological malignancies has established adoptive cell therapy as a viable treatment modality. As the costs associated with patient and tumor genome sequencing continue to decrease, the rapidly evolving “omics”-level of data acquisition and processing may enable precise treatment strategies for these patients. Deconvoluting patient-specific tumor heterogeneity with the assistance of “big data” may enable clinicians and researchers to select the best candidate immunotherapy from the start, while taking proactive approaches to overcome resistance mechanisms in an adaptive tumor microenvironment [198]. The previous ~150 years of immuno-oncology research without significant clinical success has now enabled “hockey stick” growth in exploration of the safety and efficacy of immune-centric therapies in clinical trials. Just as William Coley’s fundamental discoveries have shaped modern cancer immunotherapy, so too shall current efforts influence the future of cancer treatment.

Author Contributions

R.D.C., J.C.F.J., and A.E.S. conceived the review, R.D.C. and J.C.F.J. wrote the manuscript, and A.E.S. revised. All authors have read and agreed to the published version of the manuscript.

Funding

The authors are supported, in part, by the Department of Defense Congressionally Directed Medical Research Programs (#W81XWH-17-1-0299, #W81XWH-19-1-0263, and #W81XWH-19-1-0067 to A.E.S.), Targeted Diagnostics and Therapeutics Inc. (A.E.S.), the Degregorio Family Foundation (A.E.S.), and a Pre-Doctoral Fellowship in Pharmacology/Toxicology from the PhRMA Foundation (J.C.F.). Figure 1 was created with BioRender.com.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Couzin-Frankel, J. Breakthrough of the year 2013. Cancer immunotherapy. Science 2013, 342, 1432–1433. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Challis, G.B.; Stam, H.J. The spontaneous regression of cancer. A review of cases from 1900 to 1987. Acta Oncol. 1990, 29, 545–550. [Google Scholar] [CrossRef] [PubMed]
  3. Papac, R.J. Spontaneous regression of cancer. Cancer Treat. Rev. 1996, 22, 395–423. [Google Scholar] [CrossRef]
  4. Smith, J.L.; Stehlin, J.S. Spontaneous regression of primary malignant melanomas with regional metastases. Cancer 1965, 18, 1399–1415. [Google Scholar] [CrossRef]
  5. Haridy, Y.; Witzmann, F.; Asbach, P.; Schoch, R.R.; Fröbisch, N.; Rothschild, B.M. Triassic Cancer-Osteosarcoma in a 240-Million-Year-Old Stem-Turtle. JAMA Oncol. 2019, 5, 425–426. [Google Scholar] [CrossRef] [PubMed]
  6. Coley, W.B., II. contribution to the knowledge of sarcoma. Ann. Surg. 1891, 14, 199–220. [Google Scholar] [CrossRef] [PubMed]
  7. Coley, W.B. The treatment of malignant tumors by repeated inoculations of erysipelas: With a report of ten original cases. 1. Am. J. Med. Sci. 1893, 105, 487. [Google Scholar] [CrossRef]
  8. Stevens, D.L.; Bryant, A.E. Impetigo, erysipelas and cellulitis. In Streptococcus Pyogenes: Basic Biology to Clinical Manifestations; Ferretti, J.J., Stevens, D.L., Fischetti, V.A., Eds.; University of Oklahoma Health Sciences Center: Oklahoma City, OK, USA, 2016. [Google Scholar]
  9. Fehleisen, F. Die Aetiologie des Erysipels; Theodor Fischer: Berlin, Germany, 1883. [Google Scholar]
  10. Cann, S.A.H.; Van Netten, J.P.; Van Netten, C. Dr William Coley and tumour regression: A place in history or in the future. Postgrad. Med. 2003, 79, 672–680. [Google Scholar]
  11. McCarthy, E.F. The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas. Iowa Orthop. J. 2006, 26, 154–158. [Google Scholar]
  12. Coley, W.B. The therapeutic value of the mixed toxins of the streptococcus of erysipelas and bacillus prodigiosus in the treatment of one hundred and sixty cases. Am. J. Med. Sci. 1896, 112, 251. [Google Scholar] [CrossRef] [Green Version]
  13. Coley, W.B. The Treatment of Inoperable Sarcoma by Bacterial Toxins (the Mixed Toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc. R. Soc. Med. 1910, 3, 1–48. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Johnston, B.J.; Novales, E.T. Clinical effect of Coley’s toxin. II. A seven-year study. Cancer Chemother. Rep. 1962, 21, 43–68. [Google Scholar] [PubMed]
  15. Ehrlich, P. Über den jetzigen Stand der Karzinomforschung. Ned Tijdschr Geneeskd. 1909, 5, 273–290. [Google Scholar]
  16. Burnet, F.M. The concept of immunological surveillance. Immunol. Asp. Neoplasia 1970, 13, 1–27. [Google Scholar]
  17. Thomas, L. On immunosurveillance in human cancer. Yale J. Biol. Med. 1982, 55, 329–333. [Google Scholar]
  18. Gross, L. Intradermal immunization of C3H mice against a sarcoma that originated in an animal of the same line. Cancer Res. 1943, 3, 326–333. [Google Scholar]
  19. Prehn, R.T.; Main, J.M. Immunity to methylcholanthrene-induced sarcomas. J. Natl. Cancer Inst. 1957, 18, 769–778. [Google Scholar]
  20. Shinkai, Y.; Rathbun, G.; Lam, K.P.; Oltz, E.M.; Stewart, V.; Mendelsohn, M.; Charron, J.; Datta, M.; Young, F.; Stall, A.M. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 1992, 68, 855–867. [Google Scholar] [CrossRef]
  21. Shankaran, V.; Ikeda, H.; Bruce, A.T.; White, J.M.; Swanson, P.E.; Old, L.J.; Schreiber, R.D. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001, 410, 1107–1111. [Google Scholar] [CrossRef]
  22. Cretney, E.; Takeda, K.; Yagita, H.; Glaccum, M.; Peschon, J.J.; Smyth, M.J. Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J. Immunol. 2002, 168, 1356–1361. [Google Scholar] [CrossRef] [Green Version]
  23. van den Broek, M.E.; Kägi, D.; Ossendorp, F.; Toes, R.; Vamvakas, S.; Lutz, W.K.; Melief, C.J.; Zinkernagel, R.M.; Hengartner, H. Decreased tumor surveillance in perforin-deficient mice. J. Exp. Med. 1996, 184, 1781–1790. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Mayor, P.C.; Eng, K.H.; Singel, K.L.; Abrams, S.I.; Odunsi, K.; Moysich, K.B.; Fuleihan, R.; Garabedian, E.; Lugar, P.; Ochs, H.D.; et al. Cancer in primary immunodeficiency diseases: Cancer incidence in the United States Immune Deficiency Network Registry. J. Allergy Clin. Immunol. 2018, 141, 1028–1035. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Engels, E.A.; Pfeiffer, R.M.; Fraumeni, J.F.; Kasiske, B.L.; Israni, A.K.; Snyder, J.J.; Wolfe, R.A.; Goodrich, N.P.; Bayakly, A.R.; Clarke, C.A.; et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA 2011, 306, 1891–1901. [Google Scholar] [CrossRef] [PubMed]
  26. Goedert, J.J.; Coté, T.R.; Virgo, P.; Scoppa, S.M.; Kingma, D.W.; Gail, M.H.; Jaffe, E.S.; Biggar, R.J. Spectrum of AIDS-associated malignant disorders. Lancet 1998, 351, 1833–1839. [Google Scholar] [CrossRef]
  27. Schreiber, R.D.; Old, L.J.; Smyth, M.J. Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion. Science 2011, 331, 1565–1570. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Koebel, C.M.; Vermi, W.; Swann, J.B.; Zerafa, N.; Rodig, S.J.; Old, L.J.; Smyth, M.J.; Schreiber, R.D. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 2007, 450, 903–907. [Google Scholar] [CrossRef]
  29. DuPage, M.; Mazumdar, C.; Schmidt, L.M.; Cheung, A.F.; Jacks, T. Expression of tumour-specific antigens underlies cancer immunoediting. Nature 2012, 482, 405–409. [Google Scholar] [CrossRef] [Green Version]
  30. Miescher, S.; Whiteside, T.L.; Moretta, L.; von Fliedner, V. Clonal and frequency analyses of tumor-infiltrating T lymphocytes from human solid tumors. J. Immunol. 1987, 138, 4004–4011. [Google Scholar]
  31. Li, Y.; Patel, S.P.; Roszik, J.; Qin, Y. Hypoxia-Driven Immunosuppressive Metabolites in the Tumor Microenvironment: New Approaches for Combinational Immunotherapy. Front. Immunol. 2018, 9, 1591. [Google Scholar] [CrossRef] [Green Version]
  32. Barsoum, I.B.; Koti, M.; Siemens, D.R.; Graham, C.H. Mechanisms of hypoxia-mediated immune escape in cancer. Cancer Res. 2014, 74, 7185–7190. [Google Scholar] [CrossRef] [Green Version]
  33. Fischer, K.; Hoffmann, P.; Voelkl, S.; Meidenbauer, N.; Ammer, J.; Edinger, M.; Gottfried, E.; Schwarz, S.; Rothe, G.; Hoves, S.; et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 2007, 109, 3812–3819. [Google Scholar] [CrossRef] [PubMed]
  34. Togashi, Y.; Shitara, K.; Nishikawa, H. Regulatory T cells in cancer immunosuppression—Implications for anticancer therapy. Nat. Rev. Clin. Oncol. 2019, 16, 356–371. [Google Scholar] [CrossRef] [PubMed]
  35. Butt, A.Q.; Mills, K.H.G. Immunosuppressive networks and checkpoints controlling antitumor immunity and their blockade in the development of cancer immunotherapeutics and vaccines. Oncogene 2014, 33, 4623–4631. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Sakaguchi, S.; Yamaguchi, T.; Nomura, T.; Ono, M. Regulatory T cells and immune tolerance. Cell 2008, 133, 775–787. [Google Scholar] [CrossRef] [Green Version]
  37. Gery, I.; Gershon, R.K.; Waksman, B.H. Potentiation of the T-lymphocyte response to mitogens. I. The responding cell. J. Exp. Med. 1972, 136, 128–142. [Google Scholar] [CrossRef] [Green Version]
  38. Mier, J.W.; Gallo, R.C. Purification and some characteristics of human T-cell growth factor from phytohemagglutinin-stimulated lymphocyte-conditioned media. Proc. Natl. Acad. Sci. USA 1980, 77, 6134–6138. [Google Scholar] [CrossRef] [Green Version]
  39. Welte, K.; Wang, C.Y.; Mertelsmann, R.; Venuta, S.; Feldman, S.P.; Moore, M.A. Purification of human interleukin 2 to apparent homogeneity and its molecular heterogeneity. J. Exp. Med. 1982, 156, 454–464. [Google Scholar] [CrossRef] [Green Version]
  40. Rosenberg, S.A.; Mulé, J.J.; Spiess, P.J.; Reichert, C.M.; Schwarz, S.L. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J. Exp. Med. 1985, 161, 1169–1188. [Google Scholar] [CrossRef]
  41. Eberlein, T.J.; Rosenstein, M.; Rosenberg, S.A. Regression of a disseminated syngeneic solid tumor by systemic transfer of lymphoid cells expanded in interleukin 2. J. Exp. Med. 1982, 156, 385–397. [Google Scholar] [CrossRef] [Green Version]
  42. Rosenberg, S.A.; Lotze, M.T.; Muul, L.M.; Leitman, S.; Chang, A.E.; Ettinghausen, S.E.; Matory, Y.L.; Skibber, J.M.; Shiloni, E.; Vetto, J.T. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N. Engl. J. Med. 1985, 313, 1485–1492. [Google Scholar] [CrossRef]
  43. Rosenberg, S.A.; Lotze, M.T.; Muul, L.M.; Chang, A.E.; Avis, F.P.; Leitman, S.; Linehan, W.M.; Robertson, C.N.; Lee, R.E.; Rubin, J.T. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N. Engl. J. Med. 1987, 316, 889–897. [Google Scholar] [CrossRef] [PubMed]
  44. Schwartz, R.N.; Stover, L.; Dutcher, J. Managing toxicities of high-dose interleukin-2. Oncology 2002, 16, 11–20. [Google Scholar] [PubMed]
  45. Rosenberg, S.A.; Yang, J.C.; Topalian, S.L.; Schwartzentruber, D.J.; Weber, J.S.; Parkinson, D.R.; Seipp, C.A.; Einhorn, J.H.; White, D.E. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 1994, 271, 907–913. [Google Scholar] [CrossRef] [PubMed]
  46. Dillman, R.O.; Church, C.; Oldham, R.K.; West, W.H.; Schwartzberg, L.; Birch, R. Inpatient continuous-infusion interleukin-2 in 788 patients with cancer. The National Biotherapy Study Group experience. Cancer 1993, 71, 2358–2370. [Google Scholar] [CrossRef]
  47. Lee, S.; Margolin, K. Cytokines in cancer immunotherapy. Cancers 2011, 3, 3856–3893. [Google Scholar] [CrossRef]
  48. Ku, C.C.; Murakami, M.; Sakamoto, A.; Kappler, J.; Marrack, P. Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science 2000, 288, 675–678. [Google Scholar] [CrossRef]
  49. Evans, R.; Fuller, J.A.; Christianson, G.; Krupke, D.M. IL-15 mediates anti-tumor effects after cyclophosphamide injection of tumor-bearing mice and enhances adoptive immunotherapy: The potential role of NK cell. Cell. Immunol. 1997, 178, 197. [Google Scholar] [CrossRef]
  50. Kobayashi, H.; Dubois, S.; Sato, N.; Sabzevari, H.; Sakai, Y.; Waldmann, T.A.; Tagaya, Y. Role of trans-cellular IL-15 presentation in the activation of NK cell-mediated killing, which leads to enhanced tumor immunosurveillance. Blood 2005, 105, 721–727. [Google Scholar] [CrossRef] [Green Version]
  51. Waldmann, T.A. The biology of interleukin-2 and interleukin-15: Implications for cancer therapy and vaccine design. Nat. Rev. Immunol. 2006, 6, 595–601. [Google Scholar] [CrossRef]
  52. Bessard, A.; Solé, V.; Bouchaud, G.; Quéméner, A. High antitumor activity of RLI, an interleukin-15 (IL-15)–IL-15 receptor α fusion protein, in metastatic melanoma and colorectal cancer. Mol. Cancer Ther. 2009, 8, 2736–2745. [Google Scholar] [CrossRef] [Green Version]
  53. Howie, J.W. Experiments with interferon in man: A report to the medical research council from the scientific committee on interferon. Lancet 1965, 1, 505. [Google Scholar] [PubMed]
  54. Müller, U.; Steinhoff, U.; Reis, L.F.; Hemmi, S.; Pavlovic, J.; Zinkernagel, R.M.; Aguet, M. Functional role of type I and type II interferons in antiviral defense. Science 1994, 264, 1918–1921. [Google Scholar] [CrossRef]
  55. Waldmann, T.A. Cytokines in cancer immunotherapy. Cold Spring Harb. Perspect. Biol. 2017, 10. [Google Scholar] [CrossRef] [PubMed]
  56. Cantell, K.; Hirvonen, S.; Koistinen, V. [71] Partial purification of human leukocyte interferon on a large scale. In Methods in Enzymology; Academic Press: Cambridge, MA, USA, 1981. [Google Scholar]
  57. Merigan, T.C.; Sikora, K.; Breeden, J.H.; Levy, R.; Rosenberg, S.A. Preliminary observations on the effect of human leukocyte interferon in non-Hodgkin’s lymphoma. N. Engl. J. Med. 1978, 299, 1449–1453. [Google Scholar] [CrossRef] [PubMed]
  58. Quesada, J.R.; Hersh, E.M.; Gutterman, J.U. Hairy cell leukemia: Induction of remission with alpha interferon. Blood 1983, 62 (Suppl. 1), 207. [Google Scholar] [CrossRef] [PubMed]
  59. Quesada, J.R.; Swanson, D.A.; Trindade, A.; Gutterman, J.U. Renal cell carcinoma: Antitumor effects of leukocyte interferon. Cancer Res. 1983, 43, 940–947. [Google Scholar]
  60. Krown, S.E.; Burk, M.W.; Kirkwood, J.M.; Kerr, D. Human leukocyte (alpha) interferon in metastatic malignant melanoma. Am. Cancer Soc. Phase II Trial 1984, 68, 723–726. [Google Scholar]
  61. Kirkwood, J.M.; Ibrahim, J.G.; Sondak, V.K.; Richards, J.; Flaherty, L.E.; Ernstoff, M.S.; Smith, T.J.; Rao, U.; Steele, M.; Blum, R.H. High-and low-dose interferon alfa-2b in high-risk melanoma: First analysis of intergroup trial E1690/S9111/C9190. J. Clin. Oncol. 2000, 18, 2444–2458. [Google Scholar] [CrossRef]
  62. Hercus, T.R.; Thomas, D.; Guthridge, M.A.; Ekert, P.G.; King-Scott, J.; Parker, M.W.; Lopez, A.F. The granulocyte-macrophage colony-stimulating factor receptor: Linking its structure to cell signaling and its role in disease. Blood 2009, 114, 1289–1298. [Google Scholar] [CrossRef] [Green Version]
  63. Dranoff, G.; Jaffee, E.; Lazenby, A.; Golumbek, P.; Levitsky, H.; Brose, K.; Jackson, V.; Hamada, H.; Pardoll, D.; Mulligan, R.C. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc. Natl. Acad. Sci. USA 1993, 90, 3539–3543. [Google Scholar] [CrossRef] [Green Version]
  64. Soiffer, R.; Lynch, T.; Mihm, M.; Jung, K.; Rhuda, C.; Schmollinger, J.C.; Hodi, F.S.; Liebster, L.; Lam, P.; Mentzer, S.; et al. Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor generates potent antitumor immunity in patients with metastatic melanoma. Proc. Natl. Acad. Sci. USA 1998, 95, 13141–13146. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Small, E.J.; Reese, D.M.; Um, B.; Whisenant, S.; Dixon, S.C.; Figg, W.D. Therapy of advanced prostate cancer with granulocyte macrophage colony-stimulating factor. Clin. Cancer Res. 1999, 5, 1738–1744. [Google Scholar] [PubMed]
  66. Lawson, D.H.; Lee, S.; Zhao, F.; Tarhini, A.A.; Margolin, K.A.; Ernstoff, M.S.; Atkins, M.B.; Cohen, G.I.; Whiteside, T.L.; Butterfield, L.H.; et al. Randomized, Placebo-Controlled, Phase III Trial of Yeast-Derived Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Versus Peptide Vaccination Versus GM-CSF Plus Peptide Vaccination Versus Placebo in Patients With No Evidence of Disease After Complete Surgical Resection of Locally Advanced and/or Stage IV Melanoma: A Trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E4697). J. Clin. Oncol. 2015, 33, 4066–4076. [Google Scholar] [CrossRef] [PubMed]
  67. Hodi, F.S.; Lee, S.; McDermott, D.F.; Rao, U.N.; Butterfield, L.H.; Tarhini, A.A.; Leming, P.; Puzanov, I.; Shin, D.; Kirkwood, J.M. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: A randomized clinical trial. JAMA 2014, 312, 1744–1753. [Google Scholar] [CrossRef] [Green Version]
  68. O’Day, S.J.; Atkins, M.B.; Boasberg, P. Phase II multicenter trial of maintenance biotherapy after induction concurrent Biochemotherapy for patients with metastatic melanoma. J. Clin. Oncol. 2009, 27, 6207–6212. [Google Scholar] [CrossRef]
  69. Tang, H.; Qiao, J.; Fu, Y.-X. Immunotherapy and tumor microenvironment. Cancer Lett. 2016, 370, 85–90. [Google Scholar] [CrossRef]
  70. Mortarini, R.; Piris, A.; Maurichi, A.; Molla, A.; Bersani, I.; Bono, A.; Bartoli, C.; Santinami, M.; Lombardo, C.; Ravagnani, F.; et al. Lack of terminally differentiated tumor-specific CD8+ T cells at tumor site in spite of antitumor immunity to self-antigens in human metastatic melanoma. Cancer Res. 2003, 63, 2535–2545. [Google Scholar]
  71. Deng, L.; Zhang, H.; Luan, Y.; Zhang, J.; Xing, Q.; Dong, S.; Wu, X.; Liu, M.; Wang, S. Accumulation of foxp3+ T regulatory cells in draining lymph nodes correlates with disease progression and immune suppression in colorectal cancer patients. Clin. Cancer Res. 2010, 16, 4105–4112. [Google Scholar] [CrossRef] [Green Version]
  72. Gallimore, A.; Glithero, A.; Godkin, A.; Tissot, A.C.; Plückthun, A.; Elliott, T.; Hengartner, H.; Zinkernagel, R. Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. J. Exp. Med. 1998, 187, 1383–1393. [Google Scholar] [CrossRef]
  73. Joffre, O.; Nolte, M.A.; Spörri, R.; Reis e Sousa, C. Inflammatory signals in dendritic cell activation and the induction of adaptive immunity. Immunol. Rev. 2009, 227, 234–247. [Google Scholar] [CrossRef]
  74. Shahinian, A.; Pfeffer, K.; Lee, K.P.; Kündig, T.M.; Kishihara, K.; Wakeham, A.; Kawai, K.; Ohashi, P.S.; Thompson, C.B.; Mak, T.W. Differential T cell costimulatory requirements in CD28-deficient mice. Science 1993, 261, 609–612. [Google Scholar] [CrossRef] [PubMed]
  75. Chen, L.; Flies, D.B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 2013, 13, 227–242. [Google Scholar] [CrossRef] [PubMed]
  76. Hargadon, K.M.; Johnson, C.E.; Williams, C.J. Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors. Int. Immunopharmacol. 2018, 62, 29–39. [Google Scholar] [CrossRef] [PubMed]
  77. Brunet, J.F.; Denizot, F.; Luciani, M.F.; Roux-Dosseto, M.; Suzan, M.; Mattei, M.G.; Golstein, P. A new member of the immunoglobulin superfamily—CTLA-4. Nature 1987, 328, 267–270. [Google Scholar] [CrossRef]
  78. Walunas, T.L.; Lenschow, D.J.; Bakker, C.Y.; Linsley, P.S.; Freeman, G.J.; Green, J.M.; Thompson, C.B.; Bluestone, J.A. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994, 1, 405–413. [Google Scholar] [CrossRef]
  79. Qureshi, O.S.; Zheng, Y.; Nakamura, K.; Attridge, K.; Manzotti, C.; Schmidt, E.M.; Baker, J.; Jeffery, L.E.; Kaur, S.; Briggs, Z.; et al. Trans-endocytosis of CD80 and CD86: A molecular basis for the cell-extrinsic function of CTLA-4. Science 2011, 332, 600–603. [Google Scholar] [CrossRef] [Green Version]
  80. Krummel, M.F.; Allison, J.P. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J. Exp. Med. 1995, 182, 459–465. [Google Scholar] [CrossRef] [Green Version]
  81. Tivol, E.A.; Borriello, F.; Schweitzer, A.N.; Lynch, W.P.; Bluestone, J.A.; Sharpe, A.H. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995, 3, 541–547. [Google Scholar] [CrossRef] [Green Version]
  82. Waterhouse, P.; Penninger, J.M.; Timms, E.; Wakeham, A.; Shahinian, A.; Lee, K.P.; Thompson, C.B.; Griesser, H.; Mak, T.W. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 1995, 270, 985–988. [Google Scholar] [CrossRef]
  83. Leach, D.R.; Krummel, M.F.; Allison, J.P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996, 271, 1734–1736. [Google Scholar] [CrossRef] [Green Version]
  84. Hodi, F.S.; O’Day, S.J.; McDermott, D.F.; Weber, R.W.; Sosman, J.A.; Haanen, J.B.; Gonzalez, R.; Robert, C.; Schadendorf, D.; Hassel, J.C.; et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010, 363, 711–723. [Google Scholar] [CrossRef] [PubMed]
  85. Robert, C.; Thomas, L.; Bondarenko, I.; O’Day, S.; Weber, J.; Garbe, C.; Lebbe, C.; Baurain, J.-F.; Testori, A.; Grob, J.-J.; et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 2011, 364, 2517–2526. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Schadendorf, D.; Hodi, F.S.; Robert, C.; Weber, J.S.; Margolin, K.; Hamid, O.; Patt, D.; Chen, T.-T.; Berman, D.M.; Wolchok, J.D. Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J. Clin. Oncol. 2015, 33, 1889–1894. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Darvin, P.; Toor, S.M.; Sasidharan Nair, V.; Elkord, E. Immune checkpoint inhibitors: Recent progress and potential biomarkers. Exp. Mol. Med. 2018, 50, 165. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Ishida, Y.; Agata, Y.; Shibahara, K.; Honjo, T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992, 11, 3887–3895. [Google Scholar] [CrossRef] [PubMed]
  89. Nishimura, H.; Nose, M.; Hiai, H.; Minato, N.; Honjo, T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999, 11, 141–151. [Google Scholar] [CrossRef] [Green Version]
  90. Dong, H.; Zhu, G.; Tamada, K.; Chen, L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat. Med. 1999, 5, 1365–1369. [Google Scholar] [CrossRef]
  91. Freeman, G.J.; Long, A.J.; Iwai, Y.; Bourque, K.; Chernova, T.; Nishimura, H.; Fitz, L.J.; Malenkovich, N.; Okazaki, T.; Byrne, M.C.; et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 2000, 192, 1027–1034. [Google Scholar] [CrossRef] [Green Version]
  92. Iwai, Y.; Ishida, M.; Tanaka, Y.; Okazaki, T.; Honjo, T.; Minato, N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl. Acad. Sci. USA 2002, 99, 12293–12297. [Google Scholar] [CrossRef] [Green Version]
  93. Curiel, T.J.; Wei, S.; Dong, H.; Alvarez, X.; Cheng, P.; Mottram, P.; Krzysiek, R.; Knutson, K.L.; Daniel, B.; Zimmermann, M.C.; et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat. Med. 2003, 9, 562–567. [Google Scholar] [CrossRef]
  94. Strome, S.E.; Dong, H.; Tamura, H.; Voss, S.G.; Flies, D.B.; Tamada, K.; Salomao, D.; Cheville, J.; Hirano, F.; Lin, W.; et al. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res. 2003, 63, 6501–6505. [Google Scholar]
  95. Iwai, Y.; Terawaki, S.; Honjo, T. PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int. Immunol. 2005, 17, 133–144. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Hamanishi, J.; Mandai, M.; Iwasaki, M.; Okazaki, T.; Tanaka, Y.; Yamaguchi, K.; Higuchi, T.; Yagi, H.; Takakura, K.; Minato, N.; et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc. Natl. Acad. Sci. USA 2007, 104, 3360–3365. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Brahmer, J.R.; Tykodi, S.S.; Chow, L.Q.M.; Hwu, W.-J.; Topalian, S.L.; Hwu, P.; Drake, C.G.; Camacho, L.H.; Kauh, J.; Odunsi, K.; et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 2012, 366, 2455–2465. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Topalian, S.L.; Hodi, F.S.; Brahmer, J.R.; Gettinger, S.N.; Smith, D.C.; McDermott, D.F.; Powderly, J.D.; Carvajal, R.D.; Sosman, J.A.; Atkins, M.B.; et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 2012, 366, 2443–2454. [Google Scholar] [CrossRef]
  99. Garon, E.B.; Rizvi, N.A.; Hui, R.; Leighl, N.; Balmanoukian, A.S.; Eder, J.P.; Patnaik, A.; Aggarwal, C.; Gubens, M.; Horn, L.; et al. KEYNOTE-001 Investigators Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 2015, 372, 2018–2028. [Google Scholar] [CrossRef]
  100. Weber, J.S.; D’Angelo, S.P.; Minor, D.; Hodi, F.S.; Gutzmer, R.; Neyns, B.; Hoeller, C.; Khushalani, N.I.; Miller, W.H.; Lao, C.D.; et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015, 16, 375–384. [Google Scholar] [CrossRef]
  101. Schachter, J.; Ribas, A.; Long, G.V.; Arance, A.; Grob, J.-J.; Mortier, L.; Daud, A.; Carlino, M.S.; McNeil, C.; Lotem, M.; et al. Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet 2017, 390, 1853–1862. [Google Scholar] [CrossRef]
  102. Powles, T.; Durán, I.; van der Heijden, M.S.; Loriot, Y.; Vogelzang, N.J.; De Giorgi, U.; Oudard, S.; Retz, M.M.; Castellano, D.; Bamias, A.; et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): A multicentre, open-label, phase 3 randomised controlled trial. Lancet 2018, 391, 748–757. [Google Scholar] [CrossRef]
  103. Rittmeyer, A.; Barlesi, F.; Waterkamp, D.; Park, K.; Ciardiello, F.; von Pawel, J.; Gadgeel, S.M.; Hida, T.; Kowalski, D.M.; Dols, M.C.; et al. OAK Study Group Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): A phase 3, open-label, multicentre randomised controlled trial. Lancet 2017, 389, 255–265. [Google Scholar] [CrossRef]
  104. Narayan, P.; Wahby, S.; Gao, J.J.; Amiri-Kordestani, L.; Ibrahim, A.; Bloomquist, E.; Tang, S.; Xu, Y.; Liu, J.; Fu, W.; et al. FDA Approval Summary: Atezolizumab plus paclitaxel protein-bound for the treatment of patients with advanced or metastatic TNBC whose tumors express PD-L1. Clin. Cancer Res. 2020. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Kaufman, H.L.; Russell, J.; Hamid, O.; Bhatia, S.; Terheyden, P.; D’Angelo, S.P.; Shih, K.C.; Lebbé, C.; Linette, G.P.; Milella, M.; et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: A multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016, 17, 1374–1385. [Google Scholar] [CrossRef] [Green Version]
  106. Motzer, R.J.; Tannir, N.M.; McDermott, D.F.; Arén Frontera, O.; Melichar, B.; Choueiri, T.K.; Plimack, E.R.; Barthélémy, P.; Porta, C.; George, S.; et al. CheckMate 214 Investigators Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2018, 378, 1277–1290. [Google Scholar] [CrossRef]
  107. Jenkins, R.W.; Barbie, D.A.; Flaherty, K.T. Mechanisms of resistance to immune checkpoint inhibitors. Br. J. Cancer 2018, 118, 9–16. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  108. Anderson, A.C.; Joller, N.; Kuchroo, V.K. Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity 2016, 44, 989–1004. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  109. Routy, B.; Le Chatelier, E.; Derosa, L.; Duong, C.P.M.; Alou, M.T.; Daillère, R.; Fluckiger, A.; Messaoudene, M.; Rauber, C.; Roberti, M.P.; et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018, 359, 91–97. [Google Scholar] [CrossRef] [Green Version]
  110. Gopalakrishnan, V.; Spencer, C.N.; Nezi, L.; Reuben, A.; Andrews, M.C.; Karpinets, T.V.; Prieto, P.A.; Vicente, D.; Hoffman, K.; Wei, S.C.; et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018, 359, 97–103. [Google Scholar] [CrossRef] [Green Version]
  111. Hanna, M.G.; Peters, L.C. Specific immunotherapy of established visceral micrometastases by BCG-tumor cell vaccine alone or as an adjunct to surgery. Cancer 1978, 42, 2613–2625. [Google Scholar] [CrossRef]
  112. Murray, D.R.; Cassel, W.A.; Torbin, A.H.; Olkowski, Z.L.; Moore, M.E. Viral oncolysate in the management of malignant melanoma. II. Clinical studies. Cancer 1977, 40, 680–686. [Google Scholar] [CrossRef]
  113. McIllmurray, M.B.; Embleton, M.J.; Reeves, W.G.; Langman, M.J.; Deane, M. Controlled trial of active immunotherapy in management of stage IIB malignant melanoma. Br. Med. J. 1977, 1, 540–542. [Google Scholar] [CrossRef] [Green Version]
  114. van der Bruggen, P.; Traversari, C.; Chomez, P.; Lurquin, C.; De Plaen, E.; Van den Eynde, B.; Knuth, A.; Boon, T. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 1991, 254, 1643–1647. [Google Scholar] [CrossRef] [PubMed]
  115. Cheever, M.A.; Allison, J.P.; Ferris, A.S.; Finn, O.J.; Hastings, B.M.; Hecht, T.T.; Mellman, I.; Prindiville, S.A.; Viner, J.L.; Weiner, L.M.; et al. The prioritization of cancer antigens: A national cancer institute pilot project for the acceleration of translational research. Clin. Cancer Res. 2009, 15, 5323–5337. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Thomas, R.; Al-Khadairi, G.; Roelands, J.; Hendrickx, W.; Dermime, S.; Bedognetti, D.; Decock, J. NY-ESO-1 Based Immunotherapy of Cancer: Current Perspectives. Front. Immunol. 2018, 9, 947. [Google Scholar] [CrossRef] [PubMed]
  117. Zajac, P.; Schultz-Thater, E.; Tornillo, L.; Sadowski, C.; Trella, E.; Mengus, C.; Iezzi, G.; Spagnoli, G.C. MAGE-A Antigens and Cancer Immunotherapy. Front. Med. 2017, 4, 18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  118. Turriziani, M.; Fantini, M.; Benvenuto, M. Carcinoembryonic antigen (CEA)-based cancer vaccines: Recent patents and antitumor effects from experimental models to clinical trials. Recent Pat. Anti-Cancer Drug Discov. 2012, 7, 265–296. [Google Scholar] [CrossRef]
  119. Evdokimova, V.N.; Butterfield, L.H. Alpha-fetoprotein and other tumour-associated antigens for immunotherapy of hepatocellular cancer. Expert Opin. Biol. Ther. 2008, 8, 325–336. [Google Scholar] [CrossRef] [PubMed]
  120. Westdorp, H.; Sköld, A.E.; Snijer, B.A.; Franik, S.; Mulder, S.F.; Major, P.P.; Foley, R.; Gerritsen, W.R.; de Vries, I.J.M. Immunotherapy for prostate cancer: Lessons from responses to tumor-associated antigens. Front. Immunol. 2014, 5, 191. [Google Scholar] [CrossRef] [Green Version]
  121. Scheuermann, R.H.; Racila, E. CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy. Leuk. Lymphoma 1995, 18, 385–397. [Google Scholar] [CrossRef]
  122. Ayoub, N.M.; Al-Shami, K.M.; Yaghan, R.J. Immunotherapy for HER2-positive breast cancer: Recent advances and combination therapeutic approaches. Breast Cancer (Dove Med Press) 2019, 11, 53–69. [Google Scholar] [CrossRef] [Green Version]
  123. Liu, J.-P.; Chen, W.; Schwarer, A.P.; Li, H. Telomerase in cancer immunotherapy. Biochim. Biophys. Acta 2010, 1805, 35–42. [Google Scholar] [CrossRef] [Green Version]
  124. Jiang, T.; Shi, T.; Zhang, H.; Hu, J.; Song, Y.; Wei, J.; Ren, S.; Zhou, C. Tumor neoantigens: From basic research to clinical applications. J. Hematol. Oncol. 2019, 12, 93. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Goydos, J.S.; Elder, E.; Whiteside, T.L.; Finn, O.J.; Lotze, M.T. A phase I trial of a synthetic mucin peptide vaccine. Induction of specific immune reactivity in patients with adenocarcinoma. J. Surg. Res. 1996, 63, 298–304. [Google Scholar] [CrossRef]
  126. Mukherji, B.; Chakraborty, N.G.; Yamasaki, S.; Okino, T.; Yamase, H.; Sporn, J.R.; Kurtzman, S.K.; Ergin, M.T.; Ozols, J.; Meehan, J. Induction of antigen-specific cytolytic T cells in situ in human melanoma by immunization with synthetic peptide-pulsed autologous antigen presenting cells. Proc. Natl. Acad. Sci. USA 1995, 92, 8078–8082. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Hsu, F.J.; Benike, C.; Fagnoni, F.; Liles, T.M.; Czerwinski, D.; Taidi, B.; Engleman, E.G.; Levy, R. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat. Med. 1996, 2, 52–58. [Google Scholar] [CrossRef] [PubMed]
  128. Kim, J.W.; Gulley, J.L. Poxviral vectors for cancer immunotherapy. Expert Opin. Biol. Ther. 2012, 12, 463–478. [Google Scholar] [CrossRef] [Green Version]
  129. Gallo, P.; Dharmapuri, S.; Cipriani, B.; Monaci, P. Adenovirus as vehicle for anticancer genetic immunotherapy. Gene Ther. 2005, 12 (Suppl. 1), S84–S91. [Google Scholar] [CrossRef] [Green Version]
  130. Roland, K.L.; Brenneman, K.E. Salmonella as a vaccine delivery vehicle. Expert Rev. Vaccines 2013, 12, 1033–1045. [Google Scholar] [CrossRef] [Green Version]
  131. Flickinger, J.C.; Rodeck, U.; Snook, A.E. Listeria monocytogenes as a Vector for Cancer Immunotherapy: Current Understanding and Progress. Vaccines 2018, 6, 48. [Google Scholar] [CrossRef] [Green Version]
  132. Jahanafrooz, Z.; Baradaran, B.; Mosafer, J.; Hashemzaei, M.; Rezaei, T.; Mokhtarzadeh, A.; Hamblin, M.R. Comparison of DNA and mRNA vaccines against cancer. Drug Discov. Today 2019. [Google Scholar] [CrossRef]
  133. Palucka, K.; Banchereau, J. Dendritic-cell-based therapeutic cancer vaccines. Immunity 2013, 39, 38–48. [Google Scholar] [CrossRef] [Green Version]
  134. Kantoff, P.W.; Higano, C.S.; Shore, N.D.; Berger, E.R.; Small, E.J.; Penson, D.F.; Redfern, C.H.; Ferrari, A.C.; Dreicer, R.; Sims, R.B.; et al. IMPACT Study Investigators Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 2010, 363, 411–422. [Google Scholar] [CrossRef] [Green Version]
  135. Peng, M.; Mo, Y.; Wang, Y.; Wu, P.; Zhang, Y.; Xiong, F.; Guo, C.; Wu, X.; Li, Y.; Li, X.; et al. Neoantigen vaccine: An emerging tumor immunotherapy. Mol. Cancer 2019, 18, 128. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  136. Ott, P.A.; Hu, Z.; Keskin, D.B.; Shukla, S.A.; Sun, J.; Bozym, D.J.; Zhang, W.; Luoma, A.; Giobbie-Hurder, A.; Peter, L.; et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 2017, 547, 217–221. [Google Scholar] [CrossRef] [PubMed]
  137. Keskin, D.B.; Anandappa, A.J.; Sun, J.; Tirosh, I.; Mathewson, N.D.; Li, S.; Oliveira, G.; Giobbie-Hurder, A.; Felt, K.; Gjini, E.; et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 2019, 565, 234–239. [Google Scholar] [CrossRef] [PubMed]
  138. Finn, O.J. The dawn of vaccines for cancer prevention. Nat. Rev. Immunol. 2018, 18, 183–194. [Google Scholar] [CrossRef]
  139. Chang, M.-H. Hepatitis B virus and cancer prevention. Recent Results Cancer Res. 2011, 188, 75–84. [Google Scholar] [CrossRef]
  140. Guo, F.; Cofie, L.E.; Berenson, A.B. Cervical cancer incidence in young U.S. females after human papillomavirus vaccine introduction. Am. J. Prev. Med. 2018, 55, 197–204. [Google Scholar] [CrossRef]
  141. Singh, R.; Bandyopadhyay, D. MUC1: A target molecule for cancer therapy. Cancer Biol. Ther. 2007, 6, 481–486. [Google Scholar] [CrossRef]
  142. Kimura, T.; McKolanis, J.R.; Dzubinski, L.A.; Islam, K.; Potter, D.M.; Salazar, A.M.; Schoen, R.E.; Finn, O.J. MUC1 vaccine for individuals with advanced adenoma of the colon: A cancer immunoprevention feasibility study. Cancer Prev. Res. 2013, 6, 18–26. [Google Scholar] [CrossRef] [Green Version]
  143. Lawler, S.E.; Speranza, M.-C.; Cho, C.-F.; Chiocca, E.A. Oncolytic viruses in cancer treatment: A review. JAMA Oncol. 2017, 3, 841–849. [Google Scholar] [CrossRef] [Green Version]
  144. Alvarez, C.A. NK cells impede glioblastoma virotherapy through NKp30 and NKp46 natural cytotoxicity receptors. Nat. Med. 2012, 18, 1827. [Google Scholar] [CrossRef] [Green Version]
  145. Yung, W.K.A.; Vence, L.M.; Gomez, C. Delta-24-RGD oncolytic adenovirus elicits anti-glioma immunity in an immunocompetent mouse model. PloS ONE 2014, 9, e97407. [Google Scholar]
  146. Nguyen, T.; Avci, N.G.; Shin, D.H.; Martinez, N. Tune up in situ autovaccination against solid tumors with oncolytic viruses. Cancers 2018, 10, 171. [Google Scholar] [CrossRef] [Green Version]
  147. Dock, G. The influence of complicating diseases upon leukaemia. Am. J. Med Sci. 1904, 127, 563. [Google Scholar] [CrossRef]
  148. Larson, C.; Oronsky, B.; Scicinski, J.; Fanger, G.R.; Stirn, M.; Oronsky, A.; Reid, T.R. Going viral: A review of replication-selective oncolytic adenoviruses. Oncotarget 2015, 6, 19976–19989. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  149. Andtbacka, R.H.I.; Kaufman, H.L.; Collichio, F.; Amatruda, T.; Senzer, N.; Chesney, J.; Delman, K.A.; Spitler, L.E.; Puzanov, I.; Agarwala, S.S.; et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 2015, 33, 2780–2788. [Google Scholar] [CrossRef]
  150. Rosenberg, S.A.; Restifo, N.P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015, 348, 62–68. [Google Scholar] [CrossRef] [Green Version]
  151. Cohen, J.E.; Merims, S.; Frank, S.; Engelstein, R.; Peretz, T.; Lotem, M. Adoptive cell therapy: Past, present and future. Immunotherapy 2017, 9, 183–196. [Google Scholar] [CrossRef]
  152. Mitchison, N.A. Passive transfer of transplantation immunity. Nature 1953, 171, 267–268. [Google Scholar] [CrossRef] [PubMed]
  153. Delorme, E.J.; Alexander, P. Treatment of primary fibrosarcoma in the rat with immune lymphocytes. Lancet 1964, 2, 117–120. [Google Scholar] [CrossRef]
  154. Fefer, A. Immunotherapy and chemotherapy of Moloney sarcoma virus-induced tumors in mice. Cancer Res. 1969, 29, 2177–2183. [Google Scholar] [PubMed]
  155. Morgan, D.A.; Ruscetti, F.W.; Gallo, R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science 1976, 193, 1007–1008. [Google Scholar] [CrossRef] [PubMed]
  156. Donohue, J.H.; Rosenstein, M.; Chang, A.E.; Lotze, M.T.; Robb, R.J.; Rosenberg, S.A. The systemic administration of purified interleukin 2 enhances the ability of sensitized murine lymphocytes to cure a disseminated syngeneic lymphoma. J. Immunol. 1984, 132, 2123–2128. [Google Scholar] [PubMed]
  157. Muul, L.M.; Spiess, P.J.; Director, E.P.; Rosenberg, S.A. Identification of specific cytolytic immune responses against autologous tumor in humans bearing malignant melanoma. J. Immunol. 1987, 138, 989–995. [Google Scholar] [PubMed]
  158. Rosenberg, S.A.; Spiess, P.; Lafreniere, R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 1986, 233, 1318–1321. [Google Scholar] [CrossRef]
  159. Rosenberg, S.A.; Packard, B.S.; Aebersold, P.M.; Solomon, D.; Topalian, S.L.; Toy, S.T.; Simon, P.; Lotze, M.T.; Yang, J.C.; Seipp, C.A. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N. Engl. J. Med. 1988, 319, 1676–1680. [Google Scholar] [CrossRef]
  160. Slavin, S.; Nagler, A.; Naparstek, E.; Kapelushnik, Y.; Aker, M.; Cividalli, G.; Varadi, G.; Kirschbaum, M.; Ackerstein, A.; Samuel, S.; et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998, 91, 756–763. [Google Scholar] [CrossRef] [Green Version]
  161. Dudley, M.E.; Wunderlich, J.R.; Yang, J.C. A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastatic melanoma. J. Immunother. 2002, 25, 243. [Google Scholar] [CrossRef] [Green Version]
  162. Dudley, M.E.; Wunderlich, J.R.; Robbins, P.F.; Yang, J.C.; Hwu, P.; Schwartzentruber, D.J.; Topalian, S.L.; Sherry, R.; Restifo, N.P.; Hubicki, A.M.; et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002, 298, 850–854. [Google Scholar] [CrossRef] [Green Version]
  163. Morgan, R.A.; Dudley, M.E.; Wunderlich, J.R.; Hughes, M.S.; Yang, J.C.; Sherry, R.M.; Royal, R.E.; Topalian, S.L.; Kammula, U.S.; Restifo, N.P.; et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006, 314, 126–129. [Google Scholar] [CrossRef] [Green Version]
  164. Johnson, L.A.; Morgan, R.A.; Dudley, M.E.; Cassard, L.; Yang, J.C.; Hughes, M.S.; Kammula, U.S.; Royal, R.E.; Sherry, R.M.; Wunderlich, J.R.; et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 2009, 114, 535–546. [Google Scholar] [CrossRef] [Green Version]
  165. Robbins, P.F.; Morgan, R.A.; Feldman, S.A.; Yang, J.C.; Sherry, R.M.; Dudley, M.E.; Wunderlich, J.R.; Nahvi, A.V.; Helman, L.J.; Mackall, C.L.; et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J. Clin. Oncol. 2011, 29, 917–924. [Google Scholar] [CrossRef]
  166. Pule, M.A.; Savoldo, B.; Myers, G.D.; Rossig, C.; Russell, H.V.; Dotti, G.; Huls, M.H.; Liu, E.; Gee, A.P.; Mei, Z.; et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: Persistence and antitumor activity in individuals with neuroblastoma. Nat. Med. 2008, 14, 1264–1270. [Google Scholar] [CrossRef]
  167. Parkhurst, M.R.; Yang, J.C.; Langan, R.C.; Dudley, M.E.; Nathan, D.-A.N.; Feldman, S.A.; Davis, J.L.; Morgan, R.A.; Merino, M.J.; Sherry, R.M.; et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol. Ther. 2011, 19, 620–626. [Google Scholar] [CrossRef]
  168. Robbins, P.F.; Lu, Y.-C.; El-Gamil, M.; Li, Y.F.; Gross, C.; Gartner, J.; Lin, J.C.; Teer, J.K.; Cliften, P.; Tycksen, E.; et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat. Med. 2013, 19, 747–752. [Google Scholar] [CrossRef]
  169. Tran, E.; Turcotte, S.; Gros, A.; Robbins, P.F.; Lu, Y.-C.; Dudley, M.E.; Wunderlich, J.R.; Somerville, R.P.; Hogan, K.; Hinrichs, C.S.; et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 2014, 344, 641–645. [Google Scholar] [CrossRef]
  170. Chandran, S.S.; Somerville, R.P.T.; Yang, J.C.; Sherry, R.M.; Klebanoff, C.A.; Goff, S.L.; Wunderlich, J.R.; Danforth, D.N.; Zlott, D.; Paria, B.C.; et al. Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: A single-centre, two-stage, single-arm, phase 2 study. Lancet Oncol. 2017, 18, 792–802. [Google Scholar] [CrossRef]
  171. Lo, W.; Parkhurst, M.; Robbins, P.F.; Tran, E.; Lu, Y.-C.; Jia, L.; Gartner, J.J.; Pasetto, A.; Deniger, D.; Malekzadeh, P.; et al. Immunologic Recognition of a Shared p53 Mutated Neoantigen in a Patient with Metastatic Colorectal Cancer. Cancer Immunol. Res. 2019, 7, 534–543. [Google Scholar] [CrossRef]
  172. Dudley, M.E.; Rosenberg, S.A. Adoptive cell transfer therapy. Semin. Oncol. 2007, 34, 524–531. [Google Scholar] [CrossRef] [Green Version]
  173. Hakomori, S. Aberrant glycosylation in tumors and tumor-associated carbohydrate antigens. Adv. Cancer Res. 1989, 52, 257–331. [Google Scholar]
  174. Werdelin, O.; Meldal, M.; Jensen, T. Processing of glycans on glycoprotein and glycopeptide antigens in antigen-presenting cells. Proc. Natl. Acad. Sci. USA 2002, 99, 9611–9613. [Google Scholar] [CrossRef] [Green Version]
  175. Garrido, F.; Aptsiauri, N.; Doorduijn, E.M.; Garcia Lora, A.M.; van Hall, T. The urgent need to recover MHC class I in cancers for effective immunotherapy. Curr. Opin. Immunol. 2016, 39, 44–51. [Google Scholar] [CrossRef] [Green Version]
  176. Gross, G.; Waks, T.; Eshhar, Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc. Natl. Acad. Sci. USA 1989, 86, 10024–10028. [Google Scholar] [CrossRef] [Green Version]
  177. Stancovski, I.; Schindler, D.G.; Waks, T.; Yarden, Y.; Sela, M.; Eshhar, Z. Targeting of T lymphocytes to Neu/HER2-expressing cells using chimeric single chain Fv receptors. J. Immunol. 1993, 151, 6577–6582. [Google Scholar] [PubMed]
  178. Hwu, P.; Shafer, G.E.; Treisman, J.; Schindler, D.G.; Gross, G.; Cowherd, R.; Rosenberg, S.A.; Eshhar, Z. Lysis of ovarian cancer cells by human lymphocytes redirected with a chimeric gene composed of an antibody variable region and the Fc receptor gamma chain. J. Exp. Med. 1993, 178, 361–366. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  179. Krause, A.; Guo, H.F.; Latouche, J.B.; Tan, C.; Cheung, N.K.; Sadelain, M. Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes. J. Exp. Med. 1998, 188, 619–626. [Google Scholar] [CrossRef] [Green Version]
  180. Finney, H.M.; Lawson, A.D.; Bebbington, C.R.; Weir, A.N. Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. J. Immunol. 1998, 161, 2791–2797. [Google Scholar] [PubMed]
  181. Haynes, N.M.; Trapani, J.A.; Teng, M.W.L.; Jackson, J.T.; Cerruti, L.; Jane, S.M.; Kershaw, M.H.; Smyth, M.J.; Darcy, P.K. Single-chain antigen recognition receptors that costimulate potent rejection of established experimental tumors. Blood 2002, 100, 3155–3163. [Google Scholar] [CrossRef] [Green Version]
  182. Lamers, C.H.J.; Sleijfer, S.; Vulto, A.G.; Kruit, W.H.J.; Kliffen, M.; Debets, R.; Gratama, J.W.; Stoter, G.; Oosterwijk, E. Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: First clinical experience. J. Clin. Oncol. 2006, 24, e20-2. [Google Scholar] [CrossRef]
  183. Kershaw, M.H.; Westwood, J.A.; Parker, L.L.; Wang, G.; Eshhar, Z.; Mavroukakis, S.A.; White, D.E.; Wunderlich, J.R.; Canevari, S.; Rogers-Freezer, L.; et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin. Cancer Res. 2006, 12, 6106–6115. [Google Scholar] [CrossRef] [Green Version]
  184. Till, B.G.; Jensen, M.C.; Wang, J.; Chen, E.Y.; Wood, B.L.; Greisman, H.A.; Qian, X.; James, S.E.; Raubitschek, A.; Forman, S.J.; et al. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 2008, 112, 2261–2271. [Google Scholar] [CrossRef] [Green Version]
  185. Hollyman, D.; Stefanski, J.; Przybylowski, M.; Bartido, S.; Borquez-Ojeda, O.; Taylor, C.; Yeh, R.; Capacio, V.; Olszewska, M.; Hosey, J.; et al. Manufacturing validation of biologically functional T cells targeted to CD19 antigen for autologous adoptive cell therapy. J. Immunother 2009, 32, 169–180. [Google Scholar] [CrossRef] [Green Version]
  186. Kochenderfer, J.N.; Wilson, W.H.; Janik, J.E.; Dudley, M.E.; Stetler-Stevenson, M.; Feldman, S.A.; Maric, I.; Raffeld, M.; Nathan, D.-A.N.; Lanier, B.J.; et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 2010, 116, 4099–4102. [Google Scholar] [CrossRef]
  187. Kalos, M.; Levine, B.L.; Porter, D.L.; Katz, S.; Grupp, S.A.; Bagg, A.; June, C.H. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 2011, 3, 95ra73. [Google Scholar] [CrossRef] [Green Version]
  188. Porter, D.L.; Levine, B.L.; Kalos, M.; Bagg, A.; June, C.H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 2011, 365, 725–733. [Google Scholar] [CrossRef] [Green Version]
  189. Milone, M.C.; Fish, J.D.; Carpenito, C.; Carroll, R.G.; Binder, G.K.; Teachey, D.; Samanta, M.; Lakhal, M.; Gloss, B.; Danet-Desnoyers, G.; et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol. Ther. 2009, 17, 1453–1464. [Google Scholar] [CrossRef]
  190. Shimabukuro-Vornhagen, A.; Gödel, P.; Subklewe, M.; Stemmler, H.J.; Schlößer, H.A.; Schlaak, M.; Kochanek, M.; Böll, B.; von Bergwelt-Baildon, M.S. Cytokine release syndrome. J. Immunother. Cancer 2018, 6, 56. [Google Scholar] [CrossRef] [Green Version]
  191. Kochenderfer, J.N.; Dudley, M.E.; Feldman, S.A.; Wilson, W.H.; Spaner, D.E.; Maric, I.; Stetler-Stevenson, M.; Phan, G.Q.; Hughes, M.S.; Sherry, R.M.; et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 2012, 119, 2709–2720. [Google Scholar] [CrossRef]
  192. Kochenderfer, J.N.; Dudley, M.E.; Kassim, S.H.; Somerville, R.P.T.; Carpenter, R.O.; Stetler-Stevenson, M.; Yang, J.C.; Phan, G.Q.; Hughes, M.S.; Sherry, R.M.; et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J. Clin. Oncol. 2015, 33, 540–549. [Google Scholar] [CrossRef] [Green Version]
  193. Maus, M.V.; Grupp, S.A.; Porter, D.L.; June, C.H. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 2014, 123, 2625–2635. [Google Scholar] [CrossRef]
  194. Grupp, S.A.; Kalos, M.; Barrett, D.; Aplenc, R.; Porter, D.L.; Rheingold, S.R.; Teachey, D.T.; Chew, A.; Hauck, B.; Wright, J.F.; et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 2013, 368, 1509–1518. [Google Scholar] [CrossRef] [Green Version]
  195. Lee, D.W.; Gardner, R.; Porter, D.L.; Louis, C.U.; Ahmed, N.; Jensen, M.; Grupp, S.A.; Mackall, C.L. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014, 124, 188–195. [Google Scholar] [CrossRef] [Green Version]
  196. Yeku, O.; Li, X.; Brentjens, R.J. Adoptive T-Cell Therapy for Solid Tumors. Am. Soc. Clin. Oncol. Educ. Book 2017, 37, 193–204. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  197. Baybutt, T.R.; Flickinger, J.C.; Caparosa, E.M.; Snook, A.E. Advances in Chimeric Antigen Receptor T-Cell Therapies for Solid Tumors. Clin. Pharmacol. Ther. 2019, 105, 71–78. [Google Scholar] [CrossRef] [PubMed]
  198. Mukherjee, S. Genomics-Guided Immunotherapy for Precision Medicine in Cancer. Cancer Biother. Radiopharm. 2019. [Google Scholar] [CrossRef]
Figure 1. Milestones in the History of Cancer Immunotherapy.
Figure 1. Milestones in the History of Cancer Immunotherapy.
Toxins 12 00241 g001
Table 1. Summary of active clinical trials for CAR-T cell therapy in solid tumors.
Table 1. Summary of active clinical trials for CAR-T cell therapy in solid tumors.
Antigen TargetCancer TypePhaseClinicalTrials.gov Designation
CD117Osteoid Sarcoma, Ewing SarcomaI/IINCT03356782
CD133Liver, Pancreatic, Brain, Breas, Ovarian, Colorectal, Acute Myeloid and Lymphoid LeukemiasI/IINCT02541370
Osteoid Sarcoma, Ewing SarcomaI/IINCT03356782
CD171Neuroblastoma, Ganglioneuroblastoma,INCT02311621
CEAColorectal I/IINCT02959151
Lung, Colorectal, Gastric, Breast, PancreaticINCT02349724
EGFRColorectalI/IINCT03152435
EGFRvIIIGlioma, Glioblastoma, GliosarcomaI/IINCT01454596
EpCAMColon, Esophageal, Pancreatic, Prostate, Gastric, HepaticI/IINCT03013712
EphA2GliomaI/IINCT02575261
ErbBHead and NeckI/IINCT01818323
FRαUrothelial BladderI/IINCT03185468
GD2GliomaI/IINCT03252171
NeuroblastomaI/IINCT03373097
INCT01822652
IINCT02765243
CervicalI/IINCT03356795
Osteoid Sarcoma, Ewing SarcomaI/IINCT03356782
Sarcoma, Osteosarcoma, Neuroblastoma, MelanomaINCT02107963
GPC3Hepatocellular CarcinomaI/IINCT02723942
NCT02959151
NCT03084380
HER2BreastI/IINCT02547961
SarcomaINCT00902044
IL-13Rα2Glioma, GlioblastomaINCT02208362
MesothelinPancreaticI/IINCT02959151
CervicalI/IINCT03356795
Advanced Solid TumorsI/IINCT03615313
Pancreatic, Ovarian, MesotheliomaINCT02159716
Malignant Pleural Disease, Mesothelioma, Lung, BreastINCT02414269
MUC1CervicalI/IINCT03356795
EsophagealI/IINCT03706326
Non-Small Cell LungI/IINCT03525782
Osteoid Sarcoma, Ewing SarcomaI/IINCT03356782
Intrahepatic CholangiocarcinomaI/IINCT03633773
MUC-16OvarianINCT02498912
PSMAUrothelial BladderI/IINCT03185468
CervicalI/IINCT03356795
ProstateINCT01140373

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Carlson, R.D.; Flickinger, J.C., Jr.; Snook, A.E. Talkin’ Toxins: From Coley’s to Modern Cancer Immunotherapy. Toxins 2020, 12, 241. https://doi.org/10.3390/toxins12040241

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Carlson RD, Flickinger JC Jr., Snook AE. Talkin’ Toxins: From Coley’s to Modern Cancer Immunotherapy. Toxins. 2020; 12(4):241. https://doi.org/10.3390/toxins12040241

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Carlson, Robert D., John C. Flickinger, Jr., and Adam E. Snook. 2020. "Talkin’ Toxins: From Coley’s to Modern Cancer Immunotherapy" Toxins 12, no. 4: 241. https://doi.org/10.3390/toxins12040241

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