The importance of model selection and drug schedule in developing combination cancer immunotherapy David J. Messenheimer1,2,3, Shawn M. Jensen1, Michael E. Afentoulis1, and Bernard A. Fox1,2 1Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Portland, OR USA; 2Dept. Molecular Microbiology & Immunology and Knight Cancer Institute, OHSU, Portland, OR; 3Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT USA
Recent clinical trials combining T cell agonists with checkpoint blockers have not provided increases in objective response rates that many expected based on preclinical studies. However, much of the preclinical data was developed using mouse models where both checkpoint blockers and T cell agonists, administered as single agents, have anticancer activity. Our group considers that failure of anti-PD-1 in preclinical and clinical studies is due to absence of a therapeutic immune response or a role for PD-1. In contrast, while anti-OX40 may boost a sub-therapeutic response, it fails in the absence of an immune response or when other suppressive elements are in play. To model combination immunotherapy we chose a PD-1 refractory MMTV-PyMT spontaneous orthotopically-transplanted breast cancer model where anti-OX40 had a significant (p=0.01) but non-curative effect. Concurrent addition of anti-PD-1 to anti-OX40 reduced therapeutic efficacy and was associated with acute cytokine release and upregulation of costimulatory and inhibitory (CTLA-4, TIM-3) markers on CD4+ and CD8+ T cells. In contrast, mice receiving anti-OX40 with delayed administration of anti-PD-1, but not the reverse order, had significantly (p=0.0001) improved survival with apparent cure in ~30% of treated mice. Considering the reduced efficacy of concurrent therapy was the result of increased CTLA-4 and TIM-3 expression, we treated mice with anti-OX40 and anti-PD-1 followed by administration of anti-CTLA-4 and anti-TIM-3. This combination failed to alter survival curves. These results document that the schedule of drug administration can play a critical role in determining the effectiveness of combination immunotherapy strategies. As the number of cancer vaccines, T cell agonists and drugs targeting mechanisms of immune evasion continue to grow, developing strategies that might be used to optimize the schedule of drug administration seems to be a crucial next step for the continued refinement of immunotherapy regimens and progress towards the goal to #FINISHCANCER.
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