S Aspeslagh1, D Morel2, J-C Soria3, S Postel-Vinay4. 1. Department of Medical Oncology, Institut Jules Bordet - ULB, Brussels, Belgium. 2. INSERM, UMR981, Villejuif, France. 3. INSERM, UMR981, Villejuif, France; Drug Development Department (DITEP, Gustave Roussy Cancer Campus, Paris-Saclay University, Villejuif, France. 4. INSERM, UMR981, Villejuif, France; Drug Development Department (DITEP, Gustave Roussy Cancer Campus, Paris-Saclay University, Villejuif, France. Electronic address: sophie.postel-vinay@gustaveroussy.fr.
Abstract
Background: Immune therapies have revolutionized cancer treatment over the last few years by allowing improvements in overall survival. However, the majority of patients is still primary or secondary resistant to such therapies, and enhancing sensitivity to immune therapies is therefore crucial to improve patient outcome. Several recent lines of evidence suggest that epigenetic modifiers have intrinsic immunomodulatory properties, which could be of therapeutic interest. Material and methods: We reviewed preclinical evidence and clinical studies which describe or exploit immunomodulatory properties of epigenetic agents. Experimental approaches, clinical applicability and corresponding ongoing clinical trials are described. Results: Several epigenetic modifiers, such as histone deacetylase inhibitors, DNA methyl transferase inhibitors, bromodomain inhibitors, lysine-specific histone demethylase 1 inhibitors and enhancer of zeste homolog 2 inhibitors, display intrinsic immunomodulatory properties. The latter can be achieved through the action of these drugs either on cancer cells (e.g. presentation and generation of neoantigens, induction of immunogenic cell death, modulation of cytokine secretion), on immune cells (e.g. linage, differentiation, activation status and antitumor capability), or on components of the microenvironment (e.g. regulatory T cells and macrophages). Several promising combinations, notably with immune checkpoint blockers or adoptive T-cell therapy, can be envisioned. Dedicated clinically relevant approaches for patient selection and trial design will be required to optimally develop such combinations. Conclusion: In an era where immune therapies are becoming a treatment backbone in many tumour types, epigenetic modifiers could play a crucial role in modulating tumours' immunogenicity and sensitivity to immune agents. Optimal trial design, including window of opportunity trials, will be key in the success of this approach, and clinical evaluation is ongoing.
Background: Immune therapies have revolutionized cancer treatment over the last few years by allowing improvements in overall survival. However, the majority of patients is still primary or secondary resistant to such therapies, and enhancing sensitivity to immune therapies is therefore crucial to improve patient outcome. Several recent lines of evidence suggest that epigenetic modifiers have intrinsic immunomodulatory properties, which could be of therapeutic interest. Material and methods: We reviewed preclinical evidence and clinical studies which describe or exploit immunomodulatory properties of epigenetic agents. Experimental approaches, clinical applicability and corresponding ongoing clinical trials are described. Results: Several epigenetic modifiers, such as histone deacetylase inhibitors, DNA methyl transferase inhibitors, bromodomain inhibitors, lysine-specific histone demethylase 1 inhibitors and enhancer of zeste homolog 2 inhibitors, display intrinsic immunomodulatory properties. The latter can be achieved through the action of these drugs either on cancer cells (e.g. presentation and generation of neoantigens, induction of immunogenic cell death, modulation of cytokine secretion), on immune cells (e.g. linage, differentiation, activation status and antitumor capability), or on components of the microenvironment (e.g. regulatory T cells and macrophages). Several promising combinations, notably with immune checkpoint blockers or adoptive T-cell therapy, can be envisioned. Dedicated clinically relevant approaches for patient selection and trial design will be required to optimally develop such combinations. Conclusion: In an era where immune therapies are becoming a treatment backbone in many tumour types, epigenetic modifiers could play a crucial role in modulating tumours' immunogenicity and sensitivity to immune agents. Optimal trial design, including window of opportunity trials, will be key in the success of this approach, and clinical evaluation is ongoing.
Authors: Florian Lüke; Dennis Christoph Harrer; Pan Pantziarka; Tobias Pukrop; Lina Ghibelli; Christopher Gerner; Albrecht Reichle; Daniel Heudobler Journal: Front Oncol Date: 2022-06-24 Impact factor: 5.738
Authors: Jennifer Borowsky; Koichiro Haruki; Mai Chan Lau; Andressa Dias Costa; Jochen K Lennerz; Marios Giannakis; Jonathan A Nowak; Shuji Ogino; Juha P Väyrynen; Tomotaka Ugai; Kota Arima; Annacarolina da Silva; Kristen D Felt; Melissa Zhao; Carino Gurjao; Tyler S Twombly; Kenji Fujiyoshi; Sara A Väyrynen; Tsuyoshi Hamada; Kosuke Mima; Susan Bullman; Tabitha A Harrison; Amanda I Phipps; Ulrike Peters; Kimmie Ng; Jeffrey A Meyerhardt; Mingyang Song; Edward L Giovannucci; Kana Wu; Xuehong Zhang; Gordon J Freeman; Curtis Huttenhower; Wendy S Garrett; Andrew T Chan; Barbara A Leggett; Vicki L J Whitehall; Neal Walker; Ian Brown; Mark Bettington; Reiko Nishihara; Charles S Fuchs Journal: Clin Cancer Res Date: 2021-02-25 Impact factor: 13.801
Authors: Abel H Y Tan; WenJuan Tu; Robert McCuaig; Kristine Hardy; Thomasina Donovan; Sofiya Tsimbalyuk; Jade K Forwood; Sudha Rao Journal: Front Immunol Date: 2019-06-12 Impact factor: 7.561