Immune Checkpoint Inhibitors in Cancer Therapy: State of the Art and Future Perspectives

A special issue of Current Oncology (ISSN 1718-7729).

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 73938

Special Issue Editors


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Guest Editor
Head of Breast Cancer Program at Fiona Elsey Cancer Research Institute, Ballarat, Australia
Interests: epithelial to mesenchymal transition; cancer stem cells; immune checkpoints; triple negative breast cancer

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Co-Guest Editor
Fiona Elsey Cancer Research Institute, Ballarat, Australia
Interests: colorectal cancer; gastric cancer; ovarian cancer

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Co-Guest Editor
Head of Renal cancer program at Fiona Elsey Cancer Research Institute, Ballarat, Australia
Interests: oncology, epithelial to mesenchymal transition; immune checkpoints

Special Issue Information

Dear Colleagues,

In this Special Issue, we aim to collect original studies, meta-analyses, clinical studies, reviews, and letters investigating recent advances in knowledge around immune checkpoint inhibition strategies in various cancers.

Immune checkpoint inhibitor (ICI)-based immunotherapy represents one of the most significant therapeutic innovations in the oncologic landscape to date. The recent introduction of ICIs, which mainly targets cytotoxic T lymphocyte–associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and its ligand (PD-L1), not only benefits patients with metastatic melanoma but also those with historically less responsive tumor types. However, these ICIs have their own distinctive adverse events, which are collectively named “immune-related adverse events”. The biological mechanisms contributing to these immune-related adverse events are still poorly understood and warrant further studies.

Clinical studies have shown that only a subset of cancer patients respond to ICI therapies. Better understanding of the tumor microenvironmental and immune status through biomarkers and other biological mechanisms may help to decipher the reasons behind differential responses and the development of resistance to ICI therapies. Moreover, the initial clinical trials of ICI combinations have yielded more promising results than ICI monotherapy alone. The number of checkpoints identified has been increasing in recent times. Biomarker identification and personalized treatment aimed at minimizing toxicity while maintaining therapeutic efficacy remain unmet medical needs and thus merit further research and clinical efforts.

Dr. Aparna Jayachandran
Prof. Dr. George Kannourakis
Dr. Prashanth Prithviraj
Guest Editors

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Keywords

  • immune checkpoint inhibitors
  • drug resistance
  • immune related adverse events
  • biomarkers
  • personalized treatment

Published Papers (19 papers)

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Research

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13 pages, 14556 KiB  
Article
Mapping Immune Correlates and Surfaceome Genes in BRAF Mutated Colorectal Cancers
by Esther Cabañas Morafraile, Cristina Saiz-Ladera, Cristina Nieto-Jiménez, Balázs Győrffy, Adam Nagy, Guillermo Velasco, Pedro Pérez-Segura and Alberto Ocaña
Curr. Oncol. 2023, 30(3), 2569-2581; https://doi.org/10.3390/curroncol30030196 - 21 Feb 2023
Cited by 1 | Viewed by 2330
Abstract
Despite the impressive results obtained with immunotherapy in several cancer types, a significant fraction of patients remains unresponsive to these treatments. In colorectal cancer (CRC), B-RafV600 mutations have been identified in 8–15% of the patients. In this work we interrogated a public dataset [...] Read more.
Despite the impressive results obtained with immunotherapy in several cancer types, a significant fraction of patients remains unresponsive to these treatments. In colorectal cancer (CRC), B-RafV600 mutations have been identified in 8–15% of the patients. In this work we interrogated a public dataset to explore the surfaceome of these tumors and found that several genes, such as GP2, CLDN18, AQP5, TM4SF4, NTSR1, VNN1, and CD109, were upregulated. By performing gene set enrichment analysis, we also identified a striking upregulation of genes (CD74, LAG3, HLA-DQB1, HLA-DRB5, HLA-DMA, HLA-DMB, HLA-DPB1, HLA-DRA, HLA-DOA, FCGR2B, HLA-DQA1, HLA-DRB1, and HLA-DPA1) associated with antigen processing and presentation via MHC class II. Likewise, we found a strong correlation between PD1 and PD(L)1 expression and the presence of genes encoding for proteins involved in antigen presentation such as CD74, HLA-DPA1, and LAG3. Furthermore, a similar association was observed for the presence of dendritic cells and macrophages. Finally, a low but positive relationship was observed between tumor mutational burden and neoantigen load. Our findings support the idea that a therapeutic strategy based on the targeting of PD(L)1 together with other receptors also involved in immuno-modulation, such as LAG3, could help to improve current treatments against BRAF-mutated CRC tumors. Full article
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14 pages, 1191 KiB  
Article
Prognostic Relevance of PDL1 and CA19-9 Expression in Gallbladder Cancer vs. Inflammatory Lesions
by Neetu Rawal, Supriya Awasthi, Nihar Ranjan Dash, Sunil Kumar, Prasenjit Das, Amar Ranjan, Anita Chopra, Maroof Ahmad Khan, Sundeep Saluja, Showket Hussain and Pranay Tanwar
Curr. Oncol. 2023, 30(2), 1571-1584; https://doi.org/10.3390/curroncol30020121 - 25 Jan 2023
Cited by 1 | Viewed by 1988
Abstract
Chronic inflammation in the gallbladder leading to persistent epithelium damage promotes invasive cancer. The study aimed to assess the prognostic value of PDL1 and CA19-9 markers in cancer/inflammatory lesions of the gallbladder. A total of 29 cases (19 cancer and 10 inflammatory) were [...] Read more.
Chronic inflammation in the gallbladder leading to persistent epithelium damage promotes invasive cancer. The study aimed to assess the prognostic value of PDL1 and CA19-9 markers in cancer/inflammatory lesions of the gallbladder. A total of 29 cases (19 cancer and 10 inflammatory) were included. The PDL1 protein concentration level and mRNA expression were assessed in the tissues’ lysates by ELISA and real-time PCR, respectively. PDL1 and CA19-9 concentration levels were compared and statistically related with clinico-pathological variables. The PDL1 protein level and its relative mRNA expression were correlated. Kaplan–Meir survival and Cox regression analyses were conducted for predicting prognosis. This study investigated the PDL1 and CA19-9 marker expression in both cancer and inflammatory cases of the gallbladder (p = 0.48 and p = 0.17 respectively). PDL1 protein expression was significantly associated with the hormonal profile of the cases (p = 0.04) at an optimum cut-off value of 13 pg/mL, while the CA19-9 marker expression was correlated with the status of liver metastasis (p = 0.0043) and size of the tumor (p = 0.004). A low PDL1 concentration was found when compared to the CA19-9 level among cancer cases (p = 0.12) and proportional in the inflammatory lesions (p = 0.63). A significant positive correlation was found between the PDL1 protein and its relative mRNA expressions in the inflammatory lesions (p = 0.029) when compared to cancer cases (p = 0.069). Our results showed that a protein-based assay for PDL1 expression would be more sensitive compared to RNA based assays for GBC risk stratifications. Overall survival was predicted with CA19-9 and PDL1 levels (p = 0.0074, p = 0.23, respectively). PDL1 and CA19-9 may act as a probable predictor of a poor prognosis in gallbladder cancer (GBC) cases. Full article
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17 pages, 2293 KiB  
Article
PD-L1 Activity Is Associated with Partial EMT and Metabolic Reprogramming in Carcinomas
by Srinath Muralidharan, Manas Sehgal, R. Soundharya, Susmita Mandal, Sauma Suvra Majumdar, M. Yeshwanth, Aryamaan Saha and Mohit Kumar Jolly
Curr. Oncol. 2022, 29(11), 8285-8301; https://doi.org/10.3390/curroncol29110654 - 31 Oct 2022
Cited by 9 | Viewed by 3335
Abstract
Immune evasion and metabolic reprogramming are hallmarks of cancer progression often associated with a poor prognosis and frequently present significant challenges for cancer therapies. Recent studies have highlighted the dynamic interaction between immunosuppression and the dysregulation of energy metabolism in modulating the tumor [...] Read more.
Immune evasion and metabolic reprogramming are hallmarks of cancer progression often associated with a poor prognosis and frequently present significant challenges for cancer therapies. Recent studies have highlighted the dynamic interaction between immunosuppression and the dysregulation of energy metabolism in modulating the tumor microenvironment to promote cancer aggressiveness. However, a pan-cancer association among these two hallmarks, and a potent common driver for them—epithelial-mesenchymal transition (EMT)—remains to be done. This meta-analysis across 184 publicly available transcriptomic datasets as well as The Cancer Genome Atlas (TCGA) data reveals that an enhanced PD-L1 activity signature along with other immune checkpoint markers correlate positively with a partial EMT and an elevated glycolysis signature but a reduced OXPHOS signature in many carcinomas. These trends were also recapitulated in single-cell, RNA-seq, time-course EMT induction data across cell lines. Furthermore, across multiple cancer types, concurrent enrichment of glycolysis and PD-L1 results in worse outcomes in terms of overall survival as compared to enrichment for only PD-L1 activity or expression. These results highlight potential functional synergy among these interconnected axes of cellular plasticity in enabling metastasis and multi-drug resistance in cancer. Full article
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11 pages, 485 KiB  
Article
Long-Term Toxicities of Immune Checkpoint Inhibitor (ICI) in Melanoma Patients
by Justin Tong, Adi Kartolo, Cynthia Yeung, Wilma Hopman and Tara Baetz
Curr. Oncol. 2022, 29(10), 7953-7963; https://doi.org/10.3390/curroncol29100629 - 20 Oct 2022
Cited by 9 | Viewed by 2280
Abstract
ICI therapy has greatly improved patient outcomes in melanoma, but at the cost of immune-related adverse events (irAEs). Data on the chronicity of irAEs, especially in real-world settings, are currently limited. We performed a retrospective chart review of 161 adult patients with melanoma [...] Read more.
ICI therapy has greatly improved patient outcomes in melanoma, but at the cost of immune-related adverse events (irAEs). Data on the chronicity of irAEs, especially in real-world settings, are currently limited. We performed a retrospective chart review of 161 adult patients with melanoma treated with at least one cycle of ICI regimen in the adjuvant or metastatic setting: 129 patients received PD-1 inhibitor monotherapy and 32 received dual immunotherapy. Patients were grouped by duration of irAE: permanent (no complete resolution), long-term (resolution over a period ≥ 6 months), transient (resolution over a period < 6 months), or no irAEs. A total of 283 irAEs were reported in the whole patient population. Sixty-six (41.0%) patients developed permanent irAEs, fifteen (9.3%) experienced long-term irAEs as their longest-lasting toxicity, thirty-four (21.1%) developed transient irAEs only, and forty-six (28.6%) experienced no irAEs. Permanent irAEs occurred in 21 (65.6%) patients treated with dual immunotherapy and in 45 (34.9%) patients treated with monotherapy. The majority of permanent irAEs were endocrine-related (36.0%) or skin-related (32.4%). Grade 3–4 permanent irAEs occurred in 20 (12.4%) patients and included toxicities such as adrenal insufficiency, myocarditis, and myelitis. Fifty-three (32.9%) patients were still requiring treatment for long-term or permanent irAEs 6 months or more following the completion of ICI therapy, including twenty-four patients on thyroid hormone replacement and twenty-two on oral steroids. ICI treatment was temporarily interrupted for 64 (22.6%) irAEs and permanently discontinued due to irAEs in 38 patients (13.6% of irAEs, 23.6% of patients); additionally, 4 (2.5%) patients died of irAEs. Our findings show that ICI treatment in melanoma is associated with a wide range of toxicities that can be permanent and may have long-lasting impacts on patients, which should therefore be discussed when obtaining consent for treatment. Full article
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13 pages, 1010 KiB  
Article
Routine Screening for Central and Primary Adrenal Insufficiency during Immune-Checkpoint Inhibitor Therapy: An Endocrinology Perspective for Oncologists
by Irena Druce, Karine Tawagi, Julie L. V. Shaw, Andrea Ibrahim, Heather Lochnan and Michael Ong
Curr. Oncol. 2022, 29(7), 4665-4677; https://doi.org/10.3390/curroncol29070370 - 2 Jul 2022
Cited by 7 | Viewed by 1950
Abstract
Background: Immune checkpoint inhibitor (ICI)-associated hypothalamic–pituitary–adrenal axis disruption can lead to hypocortisolism. This is a life-threatening but difficult to diagnose condition, due to its non-specific symptoms that overlap with symptoms of malignancy. Currently, there is no consensus on how to best screen asymptomatic [...] Read more.
Background: Immune checkpoint inhibitor (ICI)-associated hypothalamic–pituitary–adrenal axis disruption can lead to hypocortisolism. This is a life-threatening but difficult to diagnose condition, due to its non-specific symptoms that overlap with symptoms of malignancy. Currently, there is no consensus on how to best screen asymptomatic patients on ICI therapy for hypophysitis with serum cortisol. Methods: A retrospective chart review of patients treated with ICI in a tertiary care centre was conducted to assess the rate of screening with cortisol and whether this had an impact on diagnosis of ICI-hypophysitis in the preclinical stage. Patients were identified as having hypophysitis with an adrenocorticotropin hormone (ACTH) deficiency based on chart review of patients with cortisol values ≤ 140 nmol/L (≤5 mcg/dL). We also assessed what proportion of cortisol values were drawn at the correct time for interpretation (between 6 AM and 10 AM). Results: Two hundred and sixty-five patients had 1301 cortisol levels drawn, only 40% of which were drawn correctly (between 6 and 10 AM). Twenty-two cases of hypophysitis manifesting with ACTH deficiency were identified. Eight of these patients were being screened with cortisol following treatment and were detected in the outpatient setting. The remaining 14 patients were not screened and were diagnosed when symptomatic, after an emergency room visit or hospital admission. Sixty percent of the cortisol tests were uninterpretable as they were not drawn within the appropriate time window. Conclusion: Measuring morning serum cortisol in asymptomatic patients on ICI therapy is a fast and inexpensive way to screen for hypophysitis and should become the standard of care. Random serum cortisol measurement has no clinical value. Education needs to be provided on when to correctly perform the test and how to interpret it and we provide an algorithm for this purpose. The adoption and validation of such an algorithm as part of routine practice could significantly reduce morbidity and mortality in patients, especially as ICI therapy is becoming increasingly commonplace. Full article
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14 pages, 854 KiB  
Article
Real-World Adherence to Toxicity Management Guidelines for Immune-Related Adverse Events
by Arezou Teimouri, Laura V. Minard, Samantha N. Scott, Amanda Daniels and Stephanie Snow
Curr. Oncol. 2022, 29(5), 3104-3117; https://doi.org/10.3390/curroncol29050252 - 28 Apr 2022
Cited by 5 | Viewed by 2935
Abstract
Immune checkpoint inhibitors (ICIs) affect immunologic homeostasis, leading to immune-related adverse events (irAEs). Early irAE detection and management can prevent significant morbidity and mortality. A retrospective chart review was performed to characterize irAEs associated with nivolumab, ipilimumab, and nivolumab plus ipilimumab in adult [...] Read more.
Immune checkpoint inhibitors (ICIs) affect immunologic homeostasis, leading to immune-related adverse events (irAEs). Early irAE detection and management can prevent significant morbidity and mortality. A retrospective chart review was performed to characterize irAEs associated with nivolumab, ipilimumab, and nivolumab plus ipilimumab in adult medical oncology patients in Nova Scotia Health-Central Zone from 2013–2020, and to describe adherence to toxicity management guidelines. Diarrhea/colitis, hepatitis, pneumonitis, nephrotoxicity, and cardiotoxicity were studied. Of 129 charts reviewed, 67 patients (51.9%) experienced at least one irAE for a total of 98 irAEs and a 1.5% fatality rate. Of these irAEs, 33.7% led to an emergency room visit. Patients were admitted to hospital and steroids were used in 24.5% and 35.7% of cases, respectively. In 17.3% of irAEs, ICIs were permanently discontinued. In 20.4% of irAEs, ICIs were held, and patients were monitored; while in 18.4%, ICIs were held until the irAE was Grade 0–1 (and until steroids were tapered). Almost 47% of irAEs were managed according to guidelines (14.3% were not), and 38.8% had no documented management. Patients receiving immunotherapy frequently experience irAEs with half of irAEs having documented management adhering to guidelines. As immunotherapy indications expand, it is important to ensure irAEs are documented and managed appropriately. Full article
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8 pages, 477 KiB  
Article
Study of PD-1 Inhibitors in Combination with Chemoradiotherapy/Chemotherapy in Patients with Esophageal Squamous Carcinoma
by Tianhui Wei, Wenqi Ti, Qingxu Song and Yufeng Cheng
Curr. Oncol. 2022, 29(5), 2920-2927; https://doi.org/10.3390/curroncol29050238 - 20 Apr 2022
Cited by 3 | Viewed by 1830
Abstract
In this study, we aimed to evaluate the efficacy of PD-1 inhibitors in combination with concurrent CRT/CT for patients with inoperable ESCC in the real world and to find predictors for the efficacy of PD-1 inhibitors. Patients with unresectable ESCC were evaluated at [...] Read more.
In this study, we aimed to evaluate the efficacy of PD-1 inhibitors in combination with concurrent CRT/CT for patients with inoperable ESCC in the real world and to find predictors for the efficacy of PD-1 inhibitors. Patients with unresectable ESCC were evaluated at baseline. The clinical data of patients with ESCC who received CRT/CT with or without PD-1 inhibitor were collected and retrospectively reviewed. The objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) were analyzed statistically. A total of 96 patients with ESCC were included. As compared with a control group (n = 48), the PFS (6.0 months vs. 5.0 months, p = 0.025) and 6-month OS (70.8% vs. 47.9%, p < 0.001) were significantly longer in the ICIs group (n = 48). There were no significant differences in ORR and 12-month OS between the two groups. In addition, we found that body mass index (BMI) was associated with PFS (HR 0.85, 95% CI 0.76–0.95, and p = 0.004) and OS (HR 0.82, 95% CI 0.69–0.98, and p = 0.033) in the ICIs group. PD-1 inhibitors combined with CRT/CT is safe with acceptable complications and improved survival for patients with inoperable ESCC. CRT plus PD-1 inhibitor has superior antitumor efficacy. BMI was positively correlated with the efficacy of PD-1 inhibitors. Full article
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Review

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15 pages, 319 KiB  
Review
Molecular Mechanisms of Cutaneous Immune-Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitors
by Yi-Shan Teng and Sebastian Yu
Curr. Oncol. 2023, 30(7), 6805-6819; https://doi.org/10.3390/curroncol30070498 - 18 Jul 2023
Cited by 2 | Viewed by 1933
Abstract
Over the past few decades, immune checkpoint inhibitors (ICIs) have emerged as promising therapeutic options for the treatment of various cancers. These novel treatments effectively target key mediators of immune checkpoint pathways. Currently, ICIs primarily consist of monoclonal antibodies that specifically block cytotoxic [...] Read more.
Over the past few decades, immune checkpoint inhibitors (ICIs) have emerged as promising therapeutic options for the treatment of various cancers. These novel treatments effectively target key mediators of immune checkpoint pathways. Currently, ICIs primarily consist of monoclonal antibodies that specifically block cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and lymphocyte activation gene 3 protein (LAG-3). Despite the notable efficacy of ICIs in cancer treatment, they can also trigger immune-related adverse events (irAEs), which present as autoimmune-like or inflammatory conditions. IrAEs have the potential to affect multiple organ systems, with cutaneous toxicities being the most commonly observed. Although cutaneous irAEs are typically of low-grade severity and can usually be managed effectively, there are cases where severe irAEs can become life-threatening. Therefore, early recognition and a comprehensive understanding of the mechanisms underlying cutaneous irAEs are crucial for improving clinical outcomes in cancer patients. However, the precise pathogenesis of cutaneous irAEs remains unclear. This review focuses on the skin manifestations induced by ICIs, the prognosis related to cutaneous irAEs, and the exploration of potential mechanisms involved in cutaneous irAEs. Full article
26 pages, 732 KiB  
Review
Immunotherapy in Prostate Cancer: State of Art and New Therapeutic Perspectives
by Felicia Maria Maselli, Francesco Giuliani, Carmelo Laface, Martina Perrone, Assunta Melaccio, Pierluigi De Santis, Anna Natalizia Santoro, Chiara Guarini, Maria Laura Iaia and Palma Fedele
Curr. Oncol. 2023, 30(6), 5769-5794; https://doi.org/10.3390/curroncol30060432 - 13 Jun 2023
Cited by 2 | Viewed by 2513
Abstract
Prostate cancer (PC) is the most common type of tumor in men. In the early stage of the disease, it is sensitive to androgen deprivation therapy. In patients with metastatic castration-sensitive prostate cancer (mHSPC), chemotherapy and second-generation androgen receptor therapy have led to [...] Read more.
Prostate cancer (PC) is the most common type of tumor in men. In the early stage of the disease, it is sensitive to androgen deprivation therapy. In patients with metastatic castration-sensitive prostate cancer (mHSPC), chemotherapy and second-generation androgen receptor therapy have led to increased survival. However, despite advances in the management of mHSPC, castration resistance is unavoidable and many patients develop metastatic castration-resistant disease (mCRPC). In the past few decades, immunotherapy has dramatically changed the oncology landscape and has increased the survival rate of many types of cancer. However, immunotherapy in prostate cancer has not yet given the revolutionary results it has in other types of tumors. Research into new treatments is very important for patients with mCRPC because of its poor prognosis. In this review, we focus on the reasons for the apparent intrinsic resistance of prostate cancer to immunotherapy, the possibilities for overcoming this resistance, and the clinical evidence and new therapeutic perspectives regarding immunotherapy in prostate cancer with a look toward the future. Full article
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24 pages, 2227 KiB  
Review
Adverse Effects of Immune-Checkpoint Inhibitors: A Comprehensive Imaging-Oriented Review
by Carlo Augusto Mallio, Caterina Bernetti, Laura Cea, Andrea Buoso, Massimo Stiffi, Daniele Vertulli, Federico Greco and Bruno Beomonte Zobel
Curr. Oncol. 2023, 30(5), 4700-4723; https://doi.org/10.3390/curroncol30050355 - 3 May 2023
Cited by 5 | Viewed by 2773
Abstract
Immune-checkpoint inhibitors (ICIs) are immunomodulatory monoclonal antibodies, which increase antitumor immunity of the host and facilitate T-cell-mediated actions against tumors. These medications have been used in recent years as a weapon against advanced stage malignancies, such as melanoma, renal cell carcinoma, lymphoma, small [...] Read more.
Immune-checkpoint inhibitors (ICIs) are immunomodulatory monoclonal antibodies, which increase antitumor immunity of the host and facilitate T-cell-mediated actions against tumors. These medications have been used in recent years as a weapon against advanced stage malignancies, such as melanoma, renal cell carcinoma, lymphoma, small or non-small cell lung cancer, and colorectal cancer. Unfortunately, they are not free from possible adverse effects (immune-related adverse events—irAEs) that mainly affect skin, gastrointestinal, hepatic, and endocrine systems. Early diagnosis of irAEs is essential to correctly and rapidly manage patients, with ICIs suspension and therapies administration. Deep knowledge of the imaging and clinical patterns of irAEs is the key to promptly rule out other diagnoses. Here, we performed a review of the radiological signs and differential diagnosis, based on the organ involved. The aim of this review is to provide guidance to recognize the most significant radiological findings of the main irAEs, based on incidence, severity, and the role of imaging. Full article
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11 pages, 266 KiB  
Review
Metastatic Castration-Resistant Prostate Cancer, Immune Checkpoint Inhibitors, and Beyond
by Sree M. Lanka, Nicholas A. Zorko, Emmanuel S. Antonarakis and Pedro C. Barata
Curr. Oncol. 2023, 30(4), 4246-4256; https://doi.org/10.3390/curroncol30040323 - 19 Apr 2023
Cited by 7 | Viewed by 3808
Abstract
The therapeutic landscape of several genitourinary malignancies has been revolutionized by the development of immune checkpoint inhibitors (ICIs); however, the utility of immunotherapies in prostate cancer has been limited, partly due to the immunologically “cold” tumor terrain of prostate cancer. As of today, [...] Read more.
The therapeutic landscape of several genitourinary malignancies has been revolutionized by the development of immune checkpoint inhibitors (ICIs); however, the utility of immunotherapies in prostate cancer has been limited, partly due to the immunologically “cold” tumor terrain of prostate cancer. As of today, pembrolizumab is the only immune checkpoint inhibitor approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) in a select group of patients with high microsatellite instability (MSI-H), deficient mismatch repair (dMMR), or high tumor mutational burden (TMB). Looking ahead, several combinatorial approaches with ICIs involving radioligands, radiotherapy, PARP inhibitors, interleukin inhibitors, and cancer vaccines are exploring a potential synergistic effect. Furthermore, B7-H3 is an alternative checkpoint that may hold promise in adding to the treatment landscape of mCRPC. This review aims to summarize previous monotherapy and combination therapy trials of ICIs as well as novel immunotherapy combination therapeutic strategies and treatment targets in mCRPC. Full article
15 pages, 907 KiB  
Review
Pancreatic Ductal Adenocarcinoma and Immune Checkpoint Inhibitors: The Gray Curtain of Immunotherapy and Spikes of Lights
by Rita Balsano, Valentina Zanuso, Angelo Pirozzi, Lorenza Rimassa and Silvia Bozzarelli
Curr. Oncol. 2023, 30(4), 3871-3885; https://doi.org/10.3390/curroncol30040293 - 30 Mar 2023
Cited by 4 | Viewed by 3095
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a poor 5-year overall survival rate (~10%). The revolution of immunotherapy in clinical oncology has not substantially changed clinical outcome for patients with PDAC. Despite outstanding efforts, neither immune checkpoint inhibitors (ICIs) alone, nor [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a poor 5-year overall survival rate (~10%). The revolution of immunotherapy in clinical oncology has not substantially changed clinical outcome for patients with PDAC. Despite outstanding efforts, neither immune checkpoint inhibitors (ICIs) alone, nor in combination with chemotherapy or targeted therapies have shown encouraging results. This failure mirrors the lack of knowledge about the real key players of immune system senescence and the complexity of the tumor microenvironment in PDAC. However, some hope can be derived from PARP-inhibitor combinations, vaccines, and CAR-T-cells therapy. In this review, we comprehensively summarize the latest updates about the use of ICIs in PDAC, focusing on clinical evidence and ongoing studies highlighting explanations for the failure of immunotherapy and possible solutions. Full article
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12 pages, 1266 KiB  
Review
Developments in Checkpoint Inhibitor Therapy for the Management of Deficient Mismatch Repair (dMMR) Rectal Cancer
by Alan Su, Rodrigo Pedraza and Hagen Kennecke
Curr. Oncol. 2023, 30(4), 3672-3683; https://doi.org/10.3390/curroncol30040279 - 26 Mar 2023
Cited by 1 | Viewed by 2364
Abstract
Deficient mismatch repair (dMMR)/microsatellite instability-high (MSIH) colorectal cancer is resistant to conventional chemotherapy but responds to immune checkpoint inhibition (ICI). We review the standard of care in locally advanced dMMR rectal cancer with a focus on ICI. We also present a case report [...] Read more.
Deficient mismatch repair (dMMR)/microsatellite instability-high (MSIH) colorectal cancer is resistant to conventional chemotherapy but responds to immune checkpoint inhibition (ICI). We review the standard of care in locally advanced dMMR rectal cancer with a focus on ICI. We also present a case report to highlight the treatment complexities and unique challenges of this novel treatment approach. ICI can lead to immune related adverse events (irAEs), resulting in early treatment discontinuation as well as new challenges to surveillance and surgical management. Overall, neoadjuvant ICI can lead to robust treatment responses, but its impact on durable response and organ preservation requires further study. Full article
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15 pages, 766 KiB  
Review
Immune Checkpoint Inhibitors-Associated Thrombosis: Incidence, Risk Factors and Management
by Tzu-Fei Wang and Marc Carrier
Curr. Oncol. 2023, 30(3), 3032-3046; https://doi.org/10.3390/curroncol30030230 - 4 Mar 2023
Cited by 9 | Viewed by 3346
Abstract
Immune checkpoint inhibitors (ICIs) target programmed cell death (PD) 1 receptor and its ligand PD-L1, and have become an integral part of treatment regimens in many cancers including lung cancer, renal cell carcinoma, melanoma, and more. Cancer is associated with a significantly increased [...] Read more.
Immune checkpoint inhibitors (ICIs) target programmed cell death (PD) 1 receptor and its ligand PD-L1, and have become an integral part of treatment regimens in many cancers including lung cancer, renal cell carcinoma, melanoma, and more. Cancer is associated with a significantly increased risk of venous thromboembolism compared to non-cancer patients, and the risks increase further with anticancer therapies including ICIs. Cancer-associated thrombosis can lead to hospitalizations, delayed cancer treatment, and mortality. While thrombosis was not reported as a major complication in initial clinical trials leading to the approval of ICIs, emerging evidence from post-marketing studies revealed concerning risks of thrombosis in patients receiving ICIs. However, results remained heterogenous given differences in study designs and populations. Recent studies also showed that C-reactive protein dynamics might be an easily accessible biomarker for thrombosis and disease response in this population. In addition, early findings indicated that a commonly used anticoagulant for cancer-associated thrombosis, factor Xa inhibitors, might have potential synergistic antitumor effects when combined with ICIs. Herein we will review the current literature on the incidence, risk factors, and management of thrombosis in patients with cancer receiving ICIs. We aim to provide valuable information for clinicians in managing these patients. Full article
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8 pages, 247 KiB  
Review
Immunotherapy and Radiotherapy as an Antitumoral Long-Range Weapon—A Partnership with Unsolved Challenges: Dose, Fractionation, Volumes, Therapeutic Sequence
by Camil Ciprian Mireștean, Roxana Irina Iancu and Dragoș Teodor Iancu
Curr. Oncol. 2022, 29(10), 7388-7395; https://doi.org/10.3390/curroncol29100580 - 2 Oct 2022
Cited by 8 | Viewed by 2364
Abstract
Immunotherapy, the modern oncological treatment with immune checkpoint inhibitors (ICIs), has been part of the clinical practice for malignant melanoma for more than a decade. Anti-cytotoxic T-lymphocyte antigen 4 (CTLA4), anti-programmed cell death Protein 1 (PD-1), or anti programmed death-ligand 1 (PD-L1) agents [...] Read more.
Immunotherapy, the modern oncological treatment with immune checkpoint inhibitors (ICIs), has been part of the clinical practice for malignant melanoma for more than a decade. Anti-cytotoxic T-lymphocyte antigen 4 (CTLA4), anti-programmed cell death Protein 1 (PD-1), or anti programmed death-ligand 1 (PD-L1) agents are currently part of the therapeutic arsenal of metastatic or relapsed disease in numerous cancers; more recently, they have also been evaluated and validated as consolidation therapy in the advanced local stage. The combination with radiotherapy, a treatment historically considered loco-regional, changes the paradigm, offering—via synergistic effects—the potential to increase immune-mediated tumor destruction. However, the fragile balance between the tumoricidal effects through immune mechanisms and the immunosuppression induced by radiotherapy means that, in the absence of ICI, the immune-mediated potentiation effect of radiotherapy at a distance from the site of administration is rare. Through analysis of the preclinical and clinical data, especially the evidence from the PACIFIC clinical trial, we can consider that hypofractionated irradiation and reduction of the irradiated volume, in order to protect the immune-infiltrated tumor microenvironment, performed concurrently with the immunotherapy or a maximum of 2 weeks before the start of ICI treatment, could bring maximum benefits. In addition, avoiding radiation-induced lymphopenia (RILD) by protecting some anatomical lymphoid structures or large blood vessels, as well as the use of irradiation of partial tumor volumes, even in plurimetastatic disease, for the conversion of a "cold" immunological tumor into a “hot” immunological tumor are modern concepts of radiotherapy in the era of immunotherapy. Low-dose radiotherapy could also be proposed in plurimetastatic cases, the effect being different (modeling of the TME) from that of high doses per fraction irradiation (cell death with release of antigens that facilitates immune-mediated cell death). Full article
17 pages, 641 KiB  
Review
Crosstalk between Immune Checkpoint Modulators, Metabolic Reprogramming and Cellular Plasticity in Triple-Negative Breast Cancer
by Arpita Poddar, Sushma R. Rao, Prashanth Prithviraj, George Kannourakis and Aparna Jayachandran
Curr. Oncol. 2022, 29(10), 6847-6863; https://doi.org/10.3390/curroncol29100540 - 23 Sep 2022
Cited by 6 | Viewed by 3130
Abstract
Breast cancer is one of the major causes of mortality in women worldwide. Accounting for 15–20% of all breast cancer diagnoses, the triple-negative breast cancer (TNBC) subtype presents with an aggressive clinical course, heightened metastatic potential and the poorest short-term prognosis. TNBC does [...] Read more.
Breast cancer is one of the major causes of mortality in women worldwide. Accounting for 15–20% of all breast cancer diagnoses, the triple-negative breast cancer (TNBC) subtype presents with an aggressive clinical course, heightened metastatic potential and the poorest short-term prognosis. TNBC does not respond to hormonal therapy, only partially responds to radio- and chemotherapy, and has limited targeted therapy options, thus underlining the critical need for better therapeutic treatments. Although immunotherapy based on immune checkpoint inhibition is emerging as a promising treatment option for TNBC patients, activation of cellular plasticity programs such as metabolic reprogramming (MR) and epithelial-to-mesenchymal transition (EMT) causes immunotherapy to fail. In this report, we review the role of MR and EMT in immune checkpoint dysregulation in TNBCs and specifically shed light on development of novel combination treatment modalities for this challenging disease. We highlight the clinical relevance of crosstalk between MR, EMT, and immune checkpoints in TNBCs. Full article
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17 pages, 695 KiB  
Review
Immune Checkpoint Inhibitors in Cancer Therapy
by Yavar Shiravand, Faezeh Khodadadi, Seyyed Mohammad Amin Kashani, Seyed Reza Hosseini-Fard, Shadi Hosseini, Habib Sadeghirad, Rahul Ladwa, Ken O’Byrne and Arutha Kulasinghe
Curr. Oncol. 2022, 29(5), 3044-3060; https://doi.org/10.3390/curroncol29050247 - 24 Apr 2022
Cited by 253 | Viewed by 21266
Abstract
The discovery of immune checkpoint proteins such as PD-1/PDL-1 and CTLA-4 represents a significant breakthrough in the field of cancer immunotherapy. Therefore, humanized monoclonal antibodies, targeting these immune checkpoint proteins have been utilized successfully in patients with metastatic melanoma, renal cell carcinoma, head [...] Read more.
The discovery of immune checkpoint proteins such as PD-1/PDL-1 and CTLA-4 represents a significant breakthrough in the field of cancer immunotherapy. Therefore, humanized monoclonal antibodies, targeting these immune checkpoint proteins have been utilized successfully in patients with metastatic melanoma, renal cell carcinoma, head and neck cancers and non-small lung cancer. The US FDA has successfully approved three different categories of immune checkpoint inhibitors (ICIs) such as PD-1 inhibitors (Nivolumab, Pembrolizumab, and Cemiplimab), PDL-1 inhibitors (Atezolimumab, Durvalumab and Avelumab), and CTLA-4 inhibitor (Ipilimumab). Unfortunately, not all patients respond favourably to these drugs, highlighting the role of biomarkers such as Tumour mutation burden (TMB), PDL-1 expression, microbiome, hypoxia, interferon-γ, and ECM in predicting responses to ICIs-based immunotherapy. The current study aims to review the literature and updates on ICIs in cancer therapy. Full article
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16 pages, 1173 KiB  
Review
Cutaneous Adverse Events Associated with Immune Checkpoint Inhibitors: A Review Article
by Chieh-Hsun Chen, Hsin-Su Yu and Sebastian Yu
Curr. Oncol. 2022, 29(4), 2871-2886; https://doi.org/10.3390/curroncol29040234 - 18 Apr 2022
Cited by 24 | Viewed by 5950
Abstract
Immune checkpoint inhibitors (ICIs) have emerged as novel options that are effective in treating various cancers. They are monoclonal antibodies that target cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death-ligand 1 (PD-L1). However, activation of the immune [...] Read more.
Immune checkpoint inhibitors (ICIs) have emerged as novel options that are effective in treating various cancers. They are monoclonal antibodies that target cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death-ligand 1 (PD-L1). However, activation of the immune systems through ICIs may concomitantly trigger a constellation of immunologic symptoms and signs, termed immune-related adverse events (irAEs), with the skin being the most commonly involved organ. The dermatologic toxicities are observed in nearly half of the patients treated with ICIs, mainly in the form of maculopapular rash and pruritus. In the majority of cases, these cutaneous irAEs are self-limiting and manageable, and continuation of the ICIs is possible. This review provides an overview of variable ICI-mediated dermatologic reactions and describes the clinical and histopathologic presentation. Early and accurate diagnosis, recognition of severe toxicities, and appropriate management are key goals to achieve the most favorable outcomes and quality of life in cancer patients. Full article
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11 pages, 4331 KiB  
Case Report
Immune-Checkpoint Induced Skin Toxicity Masked as Squamous Cell Carcinoma: Case Report on Mimickers of Dermatological Toxicity with PD-1 Inhibition
by Sze Wah Samuel Chan, Rahul Shukla, Jennifer Ramsay, Elaine McWhirter, Paul Barnfield and Rosalyn A. Juergens
Curr. Oncol. 2023, 30(5), 4527-4537; https://doi.org/10.3390/curroncol30050342 - 27 Apr 2023
Cited by 1 | Viewed by 2218
Abstract
Background: Immune checkpoint inhibitors (ICI) are increasingly the mainstay of oncology treatment. Immune-related adverse events (irAEs) from ICI therapy differ from cytotoxic adverse events. Cutaneous irAEs are one of the most common irAEs and require careful attention to optimize the quality of life [...] Read more.
Background: Immune checkpoint inhibitors (ICI) are increasingly the mainstay of oncology treatment. Immune-related adverse events (irAEs) from ICI therapy differ from cytotoxic adverse events. Cutaneous irAEs are one of the most common irAEs and require careful attention to optimize the quality of life for oncology patients. Patient and Methods: These are two cases of patients with advanced solid-tumour malignancies treated with PD-1 inhibitor therapy. Results: Both patients developed multiple pruritic hyperkeratotic lesions, which were initially diagnosed as squamous cell carcinoma from skin biopsies. The presentation as squamous cell carcinoma was atypical and, upon further pathology review, the lesions were more in keeping with a lichenoid immune reaction stemming from the immune checkpoint blockade. With the use of oral or topical steroids and immunomodulators, the lesions resolved. Conclusions: These cases emphasize that patients on PD-1 inhibitor therapy who develop lesions resembling squamous cell carcinoma on initial pathology may require an additional pathology review to assess for immune-mediated reactions, allowing appropriate immunosuppressive therapy to be initiated. Full article
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