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Pharmaceuticals
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Immune Checkpoint Inhibitor Therapy
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Immune Checkpoint Inhibitor Therapy

A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (31 August 2021)

Special Issue Editor

Dr. Eduardo Castañón Álvarez

E-Mail Website
Guest Editor
Department of Oncology, Clínica Universidad de Navarra, 31008 Pamplona, Spain
Interests: immunotherapy; immunocheckpoints; cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Immunotherapy has provoked a paradigm shift in the treatment of cancer. Since 2013, we have known that immunotherapy is the cornerstone for the treatment of tumors such as melanoma, non-small cell lung carcinoma, head and neck carcinoma, and bladder carcinoma. Different immune checkpoints such as PD(L)1 or CTLA-4 inhibitors have become the first agents to have FDA and EMA approval for treating different carcinomas. Despite all the efforts, there are still some patients who are primarily resistant or who become resistant after being on treatment. T cell exhaustion, T regs upregulation, or MDSC activity have been proposed as mechanisms of resistance among others to immunotherapy agents. To overcome this lack of response to immunotherapy agents, different approaches such as combinations with chemotherapy, radiotherapy, or targeted therapy are under investigation. At this point, it is not only tumor mutations that are relevant to choose the proper treatment, but a deeper knowledge of the host immune system is also required.

Dr. Eduardo Castañón Álvarez
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

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Related Special Issue

Published Papers (5 papers)

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Research

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16 pages, 2845 KiB  
Article
Enzymatic Activity of CD73 Modulates Invasion of Gliomas via Epithelial–Mesenchymal Transition-Like Reprogramming
by Julia Tsiampali, Silke Neumann, Beatriz Giesen, Katharina Koch, Donata Maciaczyk, Christoph Janiak, Daniel Hänggi and Jaroslaw Maciaczyk
Pharmaceuticals 2020, 13(11), 378; https://doi.org/10.3390/ph13110378 - 11 Nov 2020
Cited by 18 | Viewed by 4145
Abstract
Glioblastoma (GBM) is the most aggressive malignant primary brain tumour in adulthood. Despite strong research efforts current treatment options have a limited impact on glioma stem-like cells (GSCs) which contribute to GBM formation, progression and chemoresistance. Invasive growth of GSCs is in part [...] Read more.
Glioblastoma (GBM) is the most aggressive malignant primary brain tumour in adulthood. Despite strong research efforts current treatment options have a limited impact on glioma stem-like cells (GSCs) which contribute to GBM formation, progression and chemoresistance. Invasive growth of GSCs is in part associated with epithelial–mesenchymal-like transition (EMT), a mechanism associated with CD73 in several cancers. Here, we show that CD73 regulates the EMT activator SNAIL1 and further investigate the role of enzymatic and non-enzymatic CD73 activity in GBM progression. Reduction of CD73 protein resulted in significant suppression of GSC viability, proliferation and clonogenicity, whereas CD73 enzymatic activity exhibited negative effects only on GSC invasion involving impaired downstream adenosine (ADO) signalling. Furthermore, application of phosphodiesterase inhibitor pentoxifylline, a potent immunomodulator, effectively inhibited ZEB1 and CD73 expression and significantly decreased viability, clonogenicity, and invasion of GSC in vitro cultures. Given the involvement of adenosine and A3 adenosine receptor in GSC invasion, we investigated the effect of the pharmacological inhibition of A3AR on GSC maintenance. Direct A3AR inhibition promoted apoptotic cell death and impaired the clonogenicity of GSC cultures. Taken together, our data indicate that CD73 is an exciting novel target in GBM therapy. Moreover, pharmacological interference, resulting in disturbed ADO signalling, provides new opportunities to innovate GBM therapy. Full article
(This article belongs to the Special Issue Immune Checkpoint Inhibitor Therapy)
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Review

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15 pages, 322 KiB  
Review
Checkpoint Inhibitor-Induced Colitis—A Clinical Overview of Incidence, Prognostic Implications and Extension of Current Treatment Options
by Carmen Portenkirchner, Peter Kienle and Karoline Horisberger
Pharmaceuticals 2021, 14(4), 367; https://doi.org/10.3390/ph14040367 - 16 Apr 2021
Cited by 18 | Viewed by 3083
Abstract
In recent years, anti-tumor immunotherapies have witnessed a major breakthrough with the emergence of immune checkpoint inhibitors (ICIs). However, the use of ICIs has also brought an era of a certain class of adverse events that differ from those of classical chemotherapies and [...] Read more.
In recent years, anti-tumor immunotherapies have witnessed a major breakthrough with the emergence of immune checkpoint inhibitors (ICIs). However, the use of ICIs has also brought an era of a certain class of adverse events that differ from those of classical chemotherapies and are more reminiscent of autoimmune diseases. This article focuses exclusively on colitis as an irAE with emphasis on vulnerable patient groups, the prognostic significance of colitis, treatment, and new therapeutic approaches that may be applicable. Colitis itself is associated with a favorable oncological outcome of the underlying disease but is as well the most common irAE leading to discontinuation of therapy. Especially in vulnerable patient groups such as IBD patients and elderly patients, colitis occurs more frequently as a side effect. It is precisely in these two patient groups that side effects more often lead to discontinuation of therapy. Therefore, in addition to the current therapy of colitis through immunosuppression, the focus should also be on new forms of therapy of severe colitis, such as fecal transplantation or ileostomy creation. Full article
(This article belongs to the Special Issue Immune Checkpoint Inhibitor Therapy)
18 pages, 609 KiB  
Review
Is There a Place for PD-1-PD-L Blockade in Acute Myeloid Leukemia?
by Laura Jimbu, Oana Mesaros, Cristian Popescu, Alexandra Neaga, Iulia Berceanu, Delia Dima, Mihaela Gaman and Mihnea Zdrenghea
Pharmaceuticals 2021, 14(4), 288; https://doi.org/10.3390/ph14040288 - 24 Mar 2021
Cited by 23 | Viewed by 4328
Abstract
Checkpoint inhibitors were a major breakthrough in the field of oncology. In September 2014, based on the KEYNOTE-001 study, the Food and Drug Administration (FDA) approved pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, for advanced or unresectable melanoma. Up until now, [...] Read more.
Checkpoint inhibitors were a major breakthrough in the field of oncology. In September 2014, based on the KEYNOTE-001 study, the Food and Drug Administration (FDA) approved pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, for advanced or unresectable melanoma. Up until now, seven PD-1/PD-ligand(L)-1 inhibitors are approved in various solid cancers and hundreds of clinical studies are currently ongoing. In hematology, PD-1 inhibitors nivolumab and pembrolizumab were approved for the treatment of relapsed/refractory (R/R) classic Hodgkin lymphoma, and later pembrolizumab was approved for R/R primary mediastinal large B-cell lymphoma. In acute myeloid leukemia (AML), the combination of hypomethylating agents and PD-1/PD-L1 inhibitors has shown promising results, worth of further investigation, while other combinations or single agent therapy have disappointing results. On the other hand, rather than in first line, these therapies could be useful in the consolidation or maintenance setting, for achieving minimal residual disease negativity. Furthermore, an interesting application could be the use of PD-1/PD-L1 inhibitors in the post allogeneic hematopoietic stem cell transplantation relapse. There are several reasons why checkpoint inhibitors are not very effective in treating AML, including the characteristics of the disease (systemic, rapidly progressive, and high tumor burden disease), low mutational burden, and dysregulation of the immune system. We here review the results of PD-1/PD-L1 inhibition in AML and discuss their potential future in the management of this disease. Full article
(This article belongs to the Special Issue Immune Checkpoint Inhibitor Therapy)
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20 pages, 1942 KiB  
Review
TIGIT/CD226 Axis Regulates Anti-Tumor Immunity
by Jinah Yeo, Minkyung Ko, Dong-Hee Lee, Yoon Park and Hyung-seung Jin
Pharmaceuticals 2021, 14(3), 200; https://doi.org/10.3390/ph14030200 - 28 Feb 2021
Cited by 80 | Viewed by 14654
Abstract
Tumors escape immune surveillance by inducing various immunosuppressive pathways, including the activation of inhibitory receptors on tumor-infiltrating T cells. While monoclonal antibodies (mAbs) blocking programmed cell death 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) have been approved [...] Read more.
Tumors escape immune surveillance by inducing various immunosuppressive pathways, including the activation of inhibitory receptors on tumor-infiltrating T cells. While monoclonal antibodies (mAbs) blocking programmed cell death 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) have been approved for multiple cancer indications, only a subset of patients benefit from immune checkpoint blockade therapies, highlighting the need for additional approaches. Therefore, the identification of new target molecules acting in distinct or complementary pathways in monotherapy or combination therapy with PD-1/PD-L1 blockade is gaining immense interest. T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) has received considerable attention in cancer immunotherapy. Recently, anti-TIGIT mAb (tiragolumab) has demonstrated promising clinical efficacy in non-small cell lung cancer treatment when combined with an anti-PD-L1 drug (Tecentriq), leading to phase III trial initiation. TIGIT is expressed mainly on T and natural killer cells; it functions as an inhibitory checkpoint receptor, thereby limiting adaptive and innate immunity. CD226 competes for binding with the same ligands with TIGIT but delivers a positive stimulatory signal to the immune cells. This review discusses the recent discoveries regarding the roles of TIGIT and CD226 in immune cell function and their potential application in cancer immunotherapy. Full article
(This article belongs to the Special Issue Immune Checkpoint Inhibitor Therapy)
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18 pages, 982 KiB  
Review
Immune Checkpoint Inhibition in Oesophago-Gastric Carcinoma
by Anica Högner and Peter Thuss-Patience
Pharmaceuticals 2021, 14(2), 151; https://doi.org/10.3390/ph14020151 - 12 Feb 2021
Cited by 18 | Viewed by 5288
Abstract
Immune checkpoint inhibitors enrich the therapeutic landscape in oesophago-gastric carcinoma. With regard to oesophageal squamous cell carcinoma (ESCC), the selective PD-1 (programmed cell death receptor 1)-inhibitor nivolumab improves disease-free survival in the adjuvant therapy setting (CHECKMATE-577). In first-line treatment, ESCC patients (pts) benefit [...] Read more.
Immune checkpoint inhibitors enrich the therapeutic landscape in oesophago-gastric carcinoma. With regard to oesophageal squamous cell carcinoma (ESCC), the selective PD-1 (programmed cell death receptor 1)-inhibitor nivolumab improves disease-free survival in the adjuvant therapy setting (CHECKMATE-577). In first-line treatment, ESCC patients (pts) benefit in overall survival (OS) from the PD-1-inhibitor pembrolizumab in combination with chemotherapy (KEYNOTE-590). In the second-line setting, nivolumab (ATTRACTION-03) and pembrolizumab (KEYNOTE-181) demonstrate a benefit in OS compared with chemotherapy. These data resulted in the approval of nivolumab for the second-line treatment of advanced ESCC pts regardless of PD-L1 (programmed cell death ligand 1) status in Europe, Asia, and the USA, and pembrolizumab for pts with PD-L1 CPS (combined positivity score) ≥ 10 in Asia and the USA. Further approvals can be expected. In gastro-oesophageal junction and gastric cancer, the addition of nivolumab to chemotherapy in first-line treatment improves OS in pts with advanced disease with PD-L1 CPS ≥ 5 (CHECKMATE-649). Additionally, pembrolizumab was non-inferior to chemotherapy for OS in PD-L1 CPS ≥ 1 pts (KEYNOTE-062). In third-line treatment, nivolumab shows benefits in OS regardless of PD-L1 expression (ATTRACTION-02) with approval in Asia, and pembrolizumab prolonged the duration of response in PD-L1 positive pts (KEYNOTE-059) with approval in the USA. We discuss the recent results of the completed phase II and III clinical trials. Full article
(This article belongs to the Special Issue Immune Checkpoint Inhibitor Therapy)
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