The Role of Immunotherapy in Hematological Malignancies

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 17764

Special Issue Editors


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Guest Editor
Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
Interests: tumor immunotherapy; multiple myeloma pathogenesis
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Guest Editor
Division of Hematology With BMT, AOU Policlinico "Vittorio Emanuele", University of Catania, Catania, Italy.

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Guest Editor
Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy
Interests: immunity; immunotherapy; leukemia
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Special Issue Information

Dear Colleagues,

Hematological malignancies have been the target of immunotherapy since the advent of allogeneic stem cell transplantation, which has shown for the first time the pros and cons of boosting immune responses against tumor cells and surrounding tissues. Allogeneic donor lymphocyte infusions have proven that it is possible to further boost allo-immune responses to re-attain remissions when the previous tumor immune surveillance has been somewhat lost. Moving from the experience with leukemias, tumor immunotherapy has recently been enriched with the introduction of different therapeutics that rely on potentiating and/or refueling immunity (checkpoint inhibitors, moAbs, and bispecific antibodies) up to the design of engineered T cells that are empowered to recognize tumor antigens through chimeric receptors (CAR-T). Indeed, hematological malignancies represent an ideal target for such approaches due to the direct access to the tumor bed by immune cells. However, a main limitation is represented by the tumor driven immune-suppressive microenvironment, which can turn off immune responses.

The aim of this Special Issue is to present the state-of-art in this field and to highlight the preclinical and clinical research strategies that are currently explored to overcome the main limitations and improve the efficacy of immune-based treatments.    

Prof. Dr. Marco Rossi
Prof. Dr. Francesco Di Raimondo
Prof. Dr. Carmine Selleri
Guest Editors

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Keywords

  • Tumor immunotherapy
  • Bispecific antibodies
  • Tumor microenvironment
  • CAR-T

Published Papers (5 papers)

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Research

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17 pages, 3346 KiB  
Article
CD19 Chimeric Antigen Receptor-Exosome Targets CD19 Positive B-lineage Acute Lymphocytic Leukemia and Induces Cytotoxicity
by Shabirul Haque and Sarah R. Vaiselbuh
Cancers 2021, 13(6), 1401; https://doi.org/10.3390/cancers13061401 - 19 Mar 2021
Cited by 35 | Viewed by 4235
Abstract
CAR-T cell therapy is not without some clinical adverse effects, namely cytokine storms, due to a massive release of cytokines when CAR-T cells multiply in the body. Our goal was to develop exosomes expressing CD19 CAR to treat CD19-positive B-cell malignancies, instead of [...] Read more.
CAR-T cell therapy is not without some clinical adverse effects, namely cytokine storms, due to a massive release of cytokines when CAR-T cells multiply in the body. Our goal was to develop exosomes expressing CD19 CAR to treat CD19-positive B-cell malignancies, instead of using whole CD19 CAR-T cells, thereby reducing the clinical risk of uncontrolled cytokine storms. Exosomes are extracellular nanovesicles (30–150 nm), composed of lipids, proteins, and nucleic acids, that carry the fingerprint of their parent cells. Exosomes are a preferred delivery system in nano-immunotherapy. Here, HEK293T parent cells were transduced with CD19 CAR plasmids and cellular CD19 CAR expression was confirmed. Exosomes (Exo-CD19 CAR) were isolated from the conditioned medium of non-transduced (WT) and CD19 CAR plasmid transduced HEK293T cells. Consequently, CD19 B-lineage leukemia cell lines were co-cultured with Exo-CD19 CAR and cell death was measured. Our data show that Exo-CD19 CAR treatment induced cytotoxicity and elevated pro-apoptotic genes in CD19-positive leukemia B-cells without inducing cell death in CD19-negative cells. Overall, the novel CD19 CAR exosomes target the CD19 surface antigens of leukemic B-cells and can induce contact-dependent cytotoxicity. Full article
(This article belongs to the Special Issue The Role of Immunotherapy in Hematological Malignancies)
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14 pages, 3138 KiB  
Article
B7-H3 Chimeric Antigen Receptor Redirected T Cells Target Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma
by Zhenguo Zi, Haihong Zhao, Huanyu Wang, Xiaojing Ma and Fang Wei
Cancers 2020, 12(12), 3815; https://doi.org/10.3390/cancers12123815 - 17 Dec 2020
Cited by 9 | Viewed by 2952
Abstract
Potent CAR-T therapies that target appropriate antigens can benefit the treatment of anaplastic lymphoma kinase-positive (ALK+) anaplastic large cell lymphoma (ALCL), which is the most common subtype of T cell lymphoma. In this study, we observed overexpression of B7-H3 in ALCL [...] Read more.
Potent CAR-T therapies that target appropriate antigens can benefit the treatment of anaplastic lymphoma kinase-positive (ALK+) anaplastic large cell lymphoma (ALCL), which is the most common subtype of T cell lymphoma. In this study, we observed overexpression of B7-H3 in ALCL cell lines derived from clinical samples and differential expression of B7-H3 in an ALK-induced T cell transformation model. A B7-H3-redirected CAR based on scFv from mAb 376.96 was developed. B7-H3 CAR-T cells showed strong cytotoxicity and cytokine secretion against target ALCL cells (SUP-M2, SU-DHL-1, and Karpas 299) in vitro. Furthermore, the B7-H3 CAR-T cells exhibited proliferative capacity and a memory phenotype upon repeated antigen stimulation. We demonstrated that B7-H3 CAR-T cells could promptly eradicate ALCL in murine xenografts. Taken together, B7-H3 is a novel and promising target in ALCLs and B7-H3 CAR-T may be a viable treatment option for ALCL. Full article
(This article belongs to the Special Issue The Role of Immunotherapy in Hematological Malignancies)
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Review

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10 pages, 1323 KiB  
Review
Checkpoint Inhibitors in Multiple Myeloma: Intriguing Potential and Unfulfilled Promises
by Omar Alkharabsheh, Zachary Trisel, Sunil Badami, Mohammed A. Aljama and M. Hasib Sidiqi
Cancers 2022, 14(1), 113; https://doi.org/10.3390/cancers14010113 - 27 Dec 2021
Cited by 5 | Viewed by 2975
Abstract
Immune dysregulation and alteration of the bone marrow microenvironment allowing plasma cells to escape immune surveillance are well-known factors associated with the proliferation of clonal plasma cells and development of multiple myeloma (MM). Whilst immunotherapeutic approaches are now commonplace in a wide spectrum [...] Read more.
Immune dysregulation and alteration of the bone marrow microenvironment allowing plasma cells to escape immune surveillance are well-known factors associated with the proliferation of clonal plasma cells and development of multiple myeloma (MM). Whilst immunotherapeutic approaches are now commonplace in a wide spectrum of malignancies, this aberration of myeloma development gives rise to the biological rationale for the use of immune checkpoint inhibitors (ICIs) in MM. However, the initial experience with these agents has been challenging with limited single agent efficacy, significant toxicity, and side effects. Herein, we review the biological and immunological aspects of MM and ICIs. We discuss the basic biology of immune checkpoint inhibitors, mechanisms of resistance, and drug failure patterns, review the published clinical trial data for ICIs in MM, and look towards the future of ICIs for MM treatment. Full article
(This article belongs to the Special Issue The Role of Immunotherapy in Hematological Malignancies)
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45 pages, 2108 KiB  
Review
The Continuum of Thyroid Disorders Related to Immune Checkpoint Inhibitors: Still Many Pending Queries
by Maria V. Deligiorgi, Sofia Sagredou, Lampros Vakkas and Dimitrios T. Trafalis
Cancers 2021, 13(21), 5277; https://doi.org/10.3390/cancers13215277 - 21 Oct 2021
Cited by 14 | Viewed by 3654
Abstract
Background: Until more data are available to shed light on the thyroid disorders related to immune checkpoint inhibitors (ICPi) implemented for the treatment of hematological malignancies, the decision-making is guided by pertinent data derived mostly from solid tumors. Methods: The present review provides [...] Read more.
Background: Until more data are available to shed light on the thyroid disorders related to immune checkpoint inhibitors (ICPi) implemented for the treatment of hematological malignancies, the decision-making is guided by pertinent data derived mostly from solid tumors. Methods: The present review provides a comprehensive and updated overview of the thyroid disorders related to ICPi, namely to inhibitors of cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death (PD) 1 (PD-1), and the ligand of the latter (PD-L1). Results: With the increasing recognition of ir thyroid disorders, many outstanding issues have emerged. Ir thyroid disorders are reminiscent of, but not identical to, thyroid autoimmunity. Interclass and intraclass ICPi differences regarding thyroid immunotoxicity await interpretation. The available data concerning the predictive value of thyroid autoantibodies for the development of ir thyroid disorders are inconclusive. Mounting data indicate an association of ir thyroid disorders with ICPi efficacy, but a causative link is still lacking. The path forward is a tailored approach, entailing: (i) the validation of tumor-specific, patient-specific, and ICPi-specific predictive factors; (ii) appropriate patient selection; (iii) the uncoupling of antitumor immunity from immunotoxicity; (iv) a multidisciplinary initiative; and (v) global registry strategies. Conclusions: Untangling and harnessing the interrelationship of immuno-oncology with endocrinology underlying the ir thyroid disorders will yield the optimal patient care. Full article
(This article belongs to the Special Issue The Role of Immunotherapy in Hematological Malignancies)
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17 pages, 901 KiB  
Review
Immunomodulatory Effects of Bendamustine in Hematopoietic Cell Transplantation
by Jessica Stokes, Megan S. Molina, Emely A. Hoffman, Richard J. Simpson and Emmanuel Katsanis
Cancers 2021, 13(7), 1702; https://doi.org/10.3390/cancers13071702 - 3 Apr 2021
Cited by 9 | Viewed by 3010
Abstract
Bendamustine (BEN) is a unique alkylating agent with efficacy against a broad range of hematological malignancies, although investigations have only recently started to delve into its immunomodulatory effects. These immunomodulatory properties of BEN in the context of hematopoietic cell transplantation (HCT) are reviewed [...] Read more.
Bendamustine (BEN) is a unique alkylating agent with efficacy against a broad range of hematological malignancies, although investigations have only recently started to delve into its immunomodulatory effects. These immunomodulatory properties of BEN in the context of hematopoietic cell transplantation (HCT) are reviewed here. Pre- and post-transplant use of BEN in multiple murine models have consistently resulted in reduced GvHD and enhanced GvL, with significant changes to key immunological cell populations, including T-cells, myeloid derived suppressor cells (MDSCs), and dendritic cells (DCs). Further, in vitro studies find that BEN enhances the suppressive function of MDSCs, skews DCs toward cDC1s, enhances Flt3 expression on DCs, increases B-cell production of IL-10, inhibits STAT3 activation, and suppresses proliferation of T- and B-cells. Overall, BEN has a broad range of immunomodulatory effects that, as they are further elucidated, may be exploited to improve clinical outcomes. As such, clinical trials are currently underway investigating new potential applications of BEN in the setting of allogeneic HCT. Full article
(This article belongs to the Special Issue The Role of Immunotherapy in Hematological Malignancies)
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