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

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

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Abstract

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
Volume5
Issue number9
DOIs
StatePublished - Sep 2017

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Immunotherapy
Apoptosis
T-Lymphocytes
Antibodies
Vaccines
CD8 Antigens
Neoplasms
Therapeutic Uses
Therapeutics
Anti-Idiotypic Antibodies
Spleen
Ligands

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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Concurrent PD-1 blockade negates the effects of OX40 agonist antibody in combination immunotherapy through inducing T-cell apoptosis. / Shrimali, Rajeev Kumar; Ahmad, Shamim; Verma, Vivek; Zeng, Peng; Ananth, Sudha; Gaur, Pankaj; Gittelman, Rachel M.; Yusko, Erik; Sanders, Catherine; Robins, Harlan; Hammond, Scott A.; Janik, John Edward; Mkrtichyan, Mikayel; Gupta, Seema; Khleif, Samir N.

In: Cancer Immunology Research, Vol. 5, No. 9, 09.2017, p. 755-766.

Research output: Contribution to journalArticle

Shrimali, RK, Ahmad, S, Verma, V, Zeng, P, Ananth, S, Gaur, P, Gittelman, RM, Yusko, E, Sanders, C, Robins, H, Hammond, SA, Janik, JE, Mkrtichyan, M, Gupta, S & Khleif, SN 2017, 'Concurrent PD-1 blockade negates the effects of OX40 agonist antibody in combination immunotherapy through inducing T-cell apoptosis', Cancer Immunology Research, vol. 5, no. 9, pp. 755-766. https://doi.org/10.1158/2326-6066.CIR-17-0292
Shrimali, Rajeev Kumar ; Ahmad, Shamim ; Verma, Vivek ; Zeng, Peng ; Ananth, Sudha ; Gaur, Pankaj ; Gittelman, Rachel M. ; Yusko, Erik ; Sanders, Catherine ; Robins, Harlan ; Hammond, Scott A. ; Janik, John Edward ; Mkrtichyan, Mikayel ; Gupta, Seema ; Khleif, Samir N. / Concurrent PD-1 blockade negates the effects of OX40 agonist antibody in combination immunotherapy through inducing T-cell apoptosis. In: Cancer Immunology Research. 2017 ; Vol. 5, No. 9. pp. 755-766.
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