Exposing Hidden Targets: Combining epigenetic and immunotherapy to overcome cancer resistance

Our plain-English summary of Exposing Hidden Targets: Combining epigenetic and immunotherapy to overcome cancer resistance, by K. Olino, T. Park, N. Ahuja (Seminars in Cancer Biology, 2020).

The study

• Authors: K. Olino, T. Park, N. Ahuja
• Journal: Seminars in Cancer Biology
• Published: 2020;65:114-122
• Type of article: Review
• Cited by: 52 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Advances in immunotherapy, most notably antibodies targeting the inhibitory immune receptors cytotoxic T-lymphocyte associated protein 4 (CTLA-4/CD152), programmed death protein 1 (PD-1/CD279) and programmed death-ligand 1 (PD-L1/B7H1/CD274) have become effective standard therapies in advanced malignancies including melanoma,1-4 merkel cell carcinoma5, urological cancers6-8, non-small cell lung cancer9-11, mis-match repair (MMR) deficient tumors12, and Hodgkin lymphoma with response rates ranging from 25 to 60% in the first and second line settings13,14. FDA approval has also been given for treatment for hepatocellular carcinoma, gastric cancer, triple negative breast cancer, cervical and head and neck cancers with response rates closer to 15 %15. Additionally, some clinical efficacy has been observed in ovarian cancer, mesothelioma, prostate cancer, diffuse large B cell lymphoma, follicular lymphoma, and both cutaneous and peripheral T-cell lymphoma. However, despite these successes, most patients will initially fail to respond to treatment and almost half of initial responders will develop secondary resistance to immunotherapy and progress. Moreover, many prevalent solid organ tumors remain resistant to immunotherapy including colorectal, pancreatic and hepatobiliary cancers. Therefore, new therapies are needed to increase both initial and durable response rates and to develop new mechanistic insights into pathways of immune resistance so that immunotherapy may become more widely available as a therapeutic option in common malignancies.

Copyright © 2020 Elsevier Ltd. All rights reserved.

In plain English

This article is a review and does not concern asbestos exposure. The authors reviewed published laboratory, animal and clinical research on combining epigenetic drugs (medicines that change which genes are switched on, such as DNA methyltransferase and histone deacetylase inhibitors) with cancer immunotherapy. Citing other studies, they noted that most patients do not respond to immunotherapy at first and almost half of initial responders later become resistant. Mesothelioma appeared only in one sentence, repeated in the abstract and introduction, listing cancers where some clinical efficacy of immunotherapy has been observed. The article gave no mesothelioma data. The review described ways epigenetic drugs may make tumors more visible to the immune system and reverse T-cell exhaustion, and noted nearly 30 active clinical trials of such combinations. In one cited mouse study, adding 5-azacytidine and entinostat to two checkpoint drugs raised survival from 40% to 100% in one tumor model. The authors concluded they remain hopeful that combined treatments will be the next frontier in cancer care. They also said newer epigenetic drugs must be more selective to limit off-target toxicity.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published studies and ongoing clinical trials (no original data collected by the authors)
• Who was studied: No study population of its own. The authors reviewed published cell-line, mouse and human clinical studies, plus a table of active, accruing and completed clinical trials combining epigenetic drugs with immunotherapy across many cancer types. There was no asbestos-exposed population.
• Exposure: Not an asbestos exposure. The 'exposure' discussed is treatment with epigenetic drugs (DNA methyltransferase inhibitors such as azacytidine, decitabine and guadecitabine, histone deacetylase inhibitors, EZH2 inhibitors, BET inhibitors) combined with immunotherapy such as anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies.
• Main results:
  • Summarizing other studies, the authors stated that most patients initially fail to respond to immunotherapy and that almost half of initial responders develop secondary resistance.
  • Mesothelioma was mentioned only in a single sentence, which appears twice (in the abstract and repeated in the introduction). That sentence lists cancers in which some clinical efficacy of immunotherapy has been observed. No mesothelioma-specific numbers or studies were given.
  • The authors reported nearly 30 currently active clinical trials combining epigenetic agents with immunotherapy.
  • In a cited mouse study (not the authors' own), anti-PD1 plus anti-CTLA-4 gave 40% survival in a CT26 model and 30% in a metastatic 4T1 model. Adding 5-azacytidine and entinostat raised survival to 100% (CT26) and 80% (4T1).
  • In a cited phase one trial in epithelial ovarian cancer combining an NY-ESO-1 vaccine with decitabine, 1 of 10 patients had a partial response and 5 had stable disease.
• The authors' conclusion: The authors concluded that they remain hopeful that combined epigenetic and immune treatment approaches will represent the next frontier in cancer care.
• Limitations the authors state:
  • In a section titled 'New directions and limitations', the authors stated that the next generation of epigenetic drugs will need to be more selective and better delivered to limit off-target toxicity.
  • The authors noted that for checkpoint blockade to work in the setting they describe, a patient must already have an appropriate CD8+ T cell population present.

Topics

Medical terms in this study, explained in our Lexicon: Immunotherapy, CTLA-4, PD-L1, Carcinoma, Stomach Cancer, Ovarian Cancer, Mesothelioma.

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• Emerging avenues in immunotherapy for the management of malignant pleural mesothelioma — S.G. Gray (2021)
• Anti-CTLA-4 therapy for malignant mesothelioma — A. Guazzelli, E. Bakker, et al. (2017)
• PD-1/PD-L1 Checkpoint Inhibitor Immunotherapy for Malignant Pleural Mesothelioma: Case Series and Literature Review — M. Zhou, N. Joshi, et al. (2021)
• Mesothelin Immunotherapy for Cancer: Ready for Prime Time? — R. Hassan, A. Thomas, et al. (2016)
• Assessment of new HDAC inhibitors for immunotherapy of malignant pleural mesothelioma — D. Bensaid, T. Blondy, et al. (2018)

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