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Monitoring immune-checkpoint blockade: response evaluation and biomarker development

Key Points

  • A subset of patients receiving immune-checkpoint inhibitor therapy develop unconventional response patterns (termed 'pseudoprogression'), in which tumour burden decreases after an initial increase, or during or after the appearance of new lesions

  • The evaluation of pseudoprogression provides new challenges in treatment monitoring and therapeutic decision-making because it cannot be evaluated with the existing response-evaluation criteria

  • The establishment of a standardized strategy to evaluate immune-related responses in patients receiving immune-checkpoint inhibitors is extremely important

  • In addition, the development of robust biomarkers to assist prediction of response and clinical benefits of immune-checkpoint inhibitor therapy is essential to further advance the field as precision immuno-oncology

  • The therapeutic activity of immune-checkpoint inhibitors is the result of a complex interplay between multiple factors in the tumour, tumour microenvironment, and immune system, requiring a collaborative approach to translate the emerging knowledge into the clinical context

Abstract

Cancer immunotherapy using immune-checkpoint blockade (ICB) has created a paradigm shift in the treatment of advanced-stage cancers. The promising antitumour activity of monoclonal antibodies targeting the immune-checkpoint proteins CTLA-4, PD-1, and PD-L1 led to regulatory approvals of these agents for the treatment of a variety of malignancies. Patients might experience clinical benefits from treatment with these agents, despite unconventional patterns of tumour response that can be misinterpreted as disease progression, warranting a new, specific approach to evaluate responses to immunotherapy. In addition, biomarkers that can predict responsiveness to ICB are being extensively investigated to further advance precision immunotherapy. Herein, we review the biological mechanisms underlying the unconventional response patterns associated with ICB, describe strategies for the objective assessments of such responses, and also highlight the ongoing efforts to identify biomarkers, in order to guide treatment with ICB. We provide state-of-the-art knowledge of immune-related response evaluations, identify unmet needs requiring further investigations, and propose future directions to maximize the benefits of ICB therapy.

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Figure 1: Ligand–receptor interactions between tumour cells and immune cells in the tumour microenvironment.
Figure 2: Response after initial increase in total tumour burden in a 77-year-old male with advanced-stage melanoma treated with ipilimumab.
Figure 3: Response after appearance of a new lesion in a 56-year-old woman with metastatic melanoma treated with ipilimumab3.
Figure 4: Key elements in biomarker development for immune-checkpoint inhibitor therapy.

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Acknowledgements

The work of M.N. has been supported by grant 1K23CA157631 from the National Cancer Institute.

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All authors researched data for the article, contributed to discussing the content of the article, and wrote, reviewed, and edited the manuscript before submission.

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Correspondence to Mizuki Nishino.

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M.N. is a consultant for Bristol-Myers Squibb, Toshiba Medical Systems and WorldCare Clinical, and has received research grants from Canon and the Merck Investigator Studies Program, and honoraria from Bayer. H.H. is a consultant for Toshiba Medical Systems, and has received research support from Canon, Konica-Minolta and Toshiba Medical Systems. F.S.H. has served as a non-paid consultant for Bristol-Myers Squibb, has received clinical trial support from Bristol-Myers Squibb, is an adviser and receives clinical trial support from Genentech and Merck, is a consultant for Amgen, EMD Serono and Novartis, and has a patent relating to tumour antigens (issued), and a patent related to the institution of major histocompatibility complex (MHC) class I polypeptide-related sequence A (MICA) as a target (licensed). N.H.R. declares no competing interests.

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Nishino, M., Ramaiya, N., Hatabu, H. et al. Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nat Rev Clin Oncol 14, 655–668 (2017). https://doi.org/10.1038/nrclinonc.2017.88

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