Simultaneous PD-1 blockade is detrimental to the anti-tumor effects mediated by the agonist OX40 antibody
Seema Gupta1, Rajeev Shrimali1, Shamim Ahmad1, Vivek Verma1, Peng Zeng1, Sudha Ananth1, PankajGaur1, Rachel Gittelman2, Erik Yusko2, CatherineSanders2, Harlan Robins2, Scott Hammond4, JohnJanik1, Mikayel Mkrtichyan1, Samir Khleif1 1Georgia Cancer Center, Augusta University, Augusta, GA, USA;2Adaptive Biotechnologies, Seattle, WA, USA; 3MedImmune LLC, Gaithersburg, MD, USA Checkpoint inhibitor antibodies (Abs) have improved anti-tumor responses in a limited number of patients. Since immune-stimulatory Abs such as anti-OX40 significantly increase the immune response, their combination with anti-PD-1 Abs is being tested in ongoing clinical trials with at least one clinical trial demonstrating lack of benefit  while the others have yet to report. The effects of these combinations on the immune repertoire in the tumor microenvironment are not well characterized. The purpose of this study was to determine the therapeutic and immune outcome of combining anti-PD-1 with anti-OX40 in an immune-primed preclinical environment. Anti-OX40 treatment resulted in significant enhancement of antigen-specific CD8+ T-cells tumor-infiltration leading to strong anti-tumor response and prolonged survival of mice. We found that simultaneous addition of anti-PD-1 to anti-OX40 abrogated these effects. Despite an increase in IFNγ-producing E7-specifc CD8+ T-cells in the spleens of mice treated with the combination, these cells underwent apoptosis in both the periphery and the tumor. Consistent with increased apoptosis, immunoSequencing analysis of the tumor and spleen T-cell population showed reduction in T- cell fraction and clonality following the addition of anti-PD-1. We further showed that delay in anti-PD- 1 addition resulted in no significant change in T-cell apoptosis, however, it did not add to the anti-tumor response of the anti-OX40 treatment. These results indicate that anti-PD-1 added at the initiation of therapy exhibits a detrimental effect on the positive outcome of anti-OX40. This result may provide an important insight into why some of the immune combination clinical trials are not producing the intended outcome.
1. Infante, et al. A phase Ib dose escalation study of the OX40 agonist MOXR0916 and the PD-L1 inhibitor atezolizumab in patients with advanced solid tumors. Presentation in ASCO Annual Meeting, 2016.
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