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Review
. 2016 Jun;8(7):821-37.
doi: 10.2217/imt-2016-0002.

Immune checkpoint inhibitor combinations in solid tumors: opportunities and challenges

Chrisann Kyi  1 , Michael A Postow  2   3
Affiliations
Review

Immune checkpoint inhibitor combinations in solid tumors: opportunities and challenges

Chrisann Kyi et al. Immunotherapy. 2016 Jun.

Abstract

The emergence of immune 'checkpoint inhibitors' such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1) has revolutionized treatment of solid tumors including melanoma, lung cancer, among many others. The goal of checkpoint inhibitor combination therapy is to improve clinical response and minimize toxicities. Rational design of checkpoint combinations considers immune-mediated mechanisms of antitumor activity: immunogenic cell death, antigen release and presentation, activation of T-cell responses, lymphocytic infiltration into tumors and depletion of immunosuppression. Potential synergistic combinations include checkpoint blockade with conventional (radiation, chemotherapy and targeted therapies) and newer immunotherapies (cancer vaccines, oncolytic viruses, among others). Reliable biomarkers are necessary to define patients who will achieve best clinical benefit with minimal toxicity in combination therapy.

Keywords: checkpoint inhibitors; combination therapies; cytotoxic T-lymphocyte antigen 4 (CTLA-4); immunotherapy; malignancy; programmed death receptor-1 (PD-1) and ligand-1 (PD-L1).

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Conflict of interest statement

Financial & competing interests disclosure

MA Postow has received research support from Bristol-Myers Squibb and has served on advisory councils. MA Postow has also received honoraria from Bristol-Myers Squibb and Merck. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

<b>Figure 1.</b>
Figure 1.. Building synergistic combinations on the foundation of PD-1 or PD-L1 blockade with both traditional and newer immune therapies.
Given the clinical success of PD-1–PD-L1 blockade in multiple solid cancers, the PD-1–PD-L1 pathway will probably become the foundation for immunotherapy combinations. Combinations of traditional therapies, including radiation and chemotherapy (top) and newer immunotherapies (bottom) are under clinical development. In developing combinations, therapies should be considered in context of the hallmark mechanisms of cancer immunotherapy: immunogenic cell death via apoptosis or necrosis; activation of professional antigen-presenting cells; activation of primed effector T cells to proliferate and exert their functions is counteracted by suppressive mechanisms in the tumor microenvironment that include Treg cells and MDSCs; increased a number of effector T lymphocytes that recognize tumor antigens; and infiltration of effector and suppressive leukocytes into tumors. Red arrows indicate mechanisms of PD-1–PD-L1 and other checkpoint inhibitors; blue arrows represent mechanisms of other immune and nonimmune therapy. The number of arrows is a demonstration of the strong potential for synergistic combinations [8,148]. MDSC: Myeloid-derived suppressor cell. Reproduced with permission from [8] © Nature Publishing Group (2015).
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References

    1. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 2012;366(26):2443–2454. - PMC - PubMed
    1. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 2013;369(2):134–144. - PMC - PubMed
    1. Hamanishi J, Mandai M, Iwasaki M, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc. Natl Acad. Sci. USA. 2007;104(9):3360–3365. - PMC - PubMed
    1. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 2012;366(26):2455–2465. - PMC - PubMed
    1. Seiwert TY, Burtness B, Weiss J, et al. A Phase 1 b study of MK-3475 in patients with human papillomavirus (HPV)-associated and non-HPV associated head and neck (H/N) cancer. J. Clin. Oncol. 2014;32(5s) Abstract 6011.

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