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Spiliopoulou  et al. Cancer Drug Resist 2024;7:2                                 Cancer
               DOI: 10.20517/cdr.2023.46
                                                                                    Drug Resistance




               Review                                                                        Open Access



               Targeting T regulatory (T ) cells in immunotherapy-
                                                          reg
               resistant cancers


                                                                             3
                                 1,2
                                               3
                                                              3
               Pavlina Spiliopoulou , Paramjit Kaur , Tracey Hammett , Giusy Di Conza , Michael Lahn 3
               1
                Department of Drug Development Program, Phase I Unit, Beatson West of Scotland Cancer Center, Glasgow G12 0YN, UK.
               2
                School of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
               3
                Department of Oncology Clinical Development, iOnctura SA, Geneva 1202, Switzerland.
               Correspondence to: Dr. Michael Lahn, Department of Oncology Clinical Development, iOnctura SA, Avenue Sécheron 15,
               Geneva 1202, Switzerland. E-mail: m.lahn@ionctura.com
               How to cite this article: Spiliopoulou  P, Kaur P, Hammett T, Di Conza G, Lahn M. Targeting T regulatory (T ) cells in
                                                                                          reg
               immunotherapy-resistant cancers. Cancer Drug Resist 2024;7:2. https://dx.doi.org/10.20517/cdr.2023.46
               Received: 13 May 2023  First Decision: 16 Jun 2023  Revised: 11 Dec 2023  Accepted: 9 Jan 2024  Published: 12 Jan 2024
               Academic Editor: Godefridus J. Peters  Copy Editor: Pei-Yun Wang  Production Editor: Pei-Yun Wang


               Abstract
               Primary or secondary (i.e., acquired) resistance is a common occurrence in cancer patients and is often associated
                                                            +
                                                                        +
                                                                 +
               with  high  numbers  of  T  regulatory  (T )  cells  (CD4 CD25 FOXP3 ).  The  approval  of  ipilimumab  and  the
                                                reg
               development of similar pharmacological agents targeting cell surface proteins on T  cells demonstrates that such
                                                                                 reg
               intervention may overcome resistance in cancer patients. Hence, the clinical development and subsequent
               approval of Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) targeting agents can serve as a prototype for similar
               agents. Such new agents aspire to be highly specific and have a reduced toxicity profile while increasing effector T
               cell function or effector T/T regulatory (T /T ) ratio. While clinical development with large molecules has shown
                                                eff
                                                   reg
               the greatest advancement, small molecule inhibitors that target immunomodulation are increasingly entering early
               clinical investigation. These new small molecule inhibitors often target specific intracellular signaling pathways
               [e.g., phosphoinositide-3-kinase delta (PI3K-δ)] that play an important role in regulating the function of T  cells.
                                                                                                    reg
               This review will summarize the lessons currently applied to develop novel clinical agents that target T  cells.
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               Keywords: Primary and secondary resistance, T regulatory cells, flow cytometry, mass cytometry,
               hyperprogression











                           © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0
                           International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing,
                           adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as
               long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and
               indicate if changes were made.

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