TY - JOUR
T1 - Concurrent PD-1 blockade negates the effects of OX40 agonist antibody in combination immunotherapy through inducing T-cell apoptosis
AU - Shrimali, Rajeev Kumar
AU - Ahmad, Shamim
AU - Verma, Vivek
AU - Zeng, Peng
AU - Ananth, Sudha
AU - Gaur, Pankaj
AU - Gittelman, Rachel M.
AU - Yusko, Erik
AU - Sanders, Catherine
AU - Robins, Harlan
AU - Hammond, Scott A.
AU - Janik, John Edward
AU - Mkrtichyan, Mikayel
AU - Gupta, Seema
AU - Khleif, Samir N.
N1 - Publisher Copyright:
©2017 AACR.
PY - 2017/9
Y1 - 2017/9
N2 - 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.
AB - 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.
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U2 - 10.1158/2326-6066.CIR-17-0292
DO - 10.1158/2326-6066.CIR-17-0292
M3 - Article
AN - SCOPUS:85028563652
SN - 2326-6066
VL - 5
SP - 755
EP - 766
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 9
ER -