Concurrent PD-1 blockade negates the effects of OX40 agonist antibody in combination immunotherapy through inducing T-cell apoptosis

Rajeev K. Shrimali, Shamim Ahmad, Vivek Verma, Peng Zeng, Sudha Ananth, Pankaj Gaur, Rachel M. Gittelman, Erik Yusko, Catherine Sanders, Harlan Robins, Scott A. Hammond, John E. Janik, Mikayel Mkrtichyan, Seema Gupta, Samir N. Khleif

Research output: Contribution to journalArticlepeer-review

126 Scopus citations


Combination therapies that depend on checkpoint inhibitor antibodies (Abs) such as for PD-1 or its ligand (PD-L1) together with immune stimulatory agonist Abs like anti-OX40 are being tested in the clinic to achieve improved antitumor effects. Here, we studied the potential therapeutic and immune effects of one such combination: Ab to PD-1 with agonist Ab to OX40/vaccine. We tested the antitumor effects of different treatment sequencing of this combination. We report that simultaneous addition of anti–PD-1 to anti-OX40 negated the antitumor effects of OX40 Ab. Antigen-specific CD8þ T-cell infiltration into the tumor was diminished, the resultant antitumor response weakened, and survival reduced. Although we observed an increase in IFNg-producing E7-specifc CD8þ T cells in the spleens of mice treated with the combination of PD-1 blockade with anti-OX40/vaccine, these cells underwent apoptosis both in the periphery and the tumor. These results indicate that anti–PD-1 added at the initiation of therapy exhibits a detrimental effect on the positive outcome of anti-OX40 agonist Ab. These findings have important implications on the design of combination immunotherapy for cancer, demonstrating the need to test treatment combination and sequencing before moving to the clinic.

Original languageEnglish (US)
Pages (from-to)755-766
Number of pages12
JournalCancer Immunology Research
Issue number9
StatePublished - Sep 2017
Externally publishedYes

Bibliographical note

Funding Information:
R.M. Gittelman is a computational biologist at Adaptive Biotechnologies. E. Yusko is a computational biologist, manager, at Adaptive Biotechnologies. C. Sanders has ownership interest in Adaptive Biotechnologies. H. Robins is cofounder of Adaptive Biotechnologies and has ownership interest in the same. S.A. Hammond has ownership interest in AstraZeneca/MedImmune. M. Mkrtichyan is a scientist at FivePrime Therapeutics Inc. S.N. Khleif reports receiving a commercial research grant from MedImmune. No potential conflicts of interest were disclosed by the other authors.

Publisher Copyright:
©2017 AACR.


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