Treatment with a VEGFR-2 antibody results in intra-tumor immune modulation and enhances antitumor efficacy of PD-L1 blockade in syngeneic murine tumor models
Yanxia Li, Marguerita O'Mahony, Ivan Inigo, Qi Li, Nelusha Amaladas, Erik Rasmussen, Thompson Doman, Jason Manro, Mary Murphy, Macrina Francisco, Gerald Hall, Michael Kalos, Ruslan Novosiadly, Bronislaw Pytowski and David Schaer Eli Lilly and Company, New York, NY & Indianapolis, IN
The relationship between tumor angiogenesis and the anti-tumor immune response is highly complex. Although the activation of VEGFR-2 by its cognate ligand VEGF has been principally implicated in tumor angiogenesis, emerging data has suggested that the VEGF/VEGFR-2 axis also mediates a suppressive effect on the anti-tumor immune response. The ability to inhibit VEGFR-2 and enhance immunotherapy with the approved antibody Ramucirumab is currently undergoing clinical testing in combination with PD-1/PD-L1 blockade and has shown promising results in early trials. However, the mechanisms underlying the immunomodulatory activity VEGFR-2 inhibition remains incompletely understood. Therefore, we performed non-clinical studies to understand at the mechanistic level how blockade of VEGFR-2 leads to the enhancement of anti-tumor immune response. Using murine EMT6 breast and MC38 colon tumor models we investigated the immunomodulatory effects of DC101, a surrogate antibody that blocks mouse VEGFR-2, and its ability to increase the anti-tumor efficacy of checkpoint inhibition. Combination of anti-VEGFR-2 with anti-PD-L1 resulted in greater anti-tumor efficacy compared to anti-PD-L1 monotherapy in both MC38 and EMT6 tumor models. Mice achieving complete tumor regressions after the combination treatment resisted tumor rechallenge demonstrating the development of immunologic memory. Analysis of changes in the tumor microenvironment by flow cytometry during combination therapy showed increased myeloid and T cell infiltration. nCounter gene expression analysis confirmed that anti-VEGFR-2 treatment enhanced inflammation and immune activation gene expression signature in monotherapy, and this effect was much more pronounced after the combination treatment. Pathway analysis highlighted that the combination effect could be attributable to enhanced innate immune response (e.g. dendritic cell maturation, antigen presentation) and T cell activation. These results were corroborated by flow cytometry, showing increased MHCI and MHCII expression on DCs and macrophages, along with increased PD-L1 expression during anti-VEGFR-2 monotherapy. Taken together, these results highlight the potential of anti-VEGFR-2 antibodies to partially ameliorate intra-tumor immune suppression, providing insights into the mechanisms by which combined VEGFR-2/PD-L1 antibody therapy leads to increased anti-tumor efficacy.
These studies were funded by Eli Lilly and Company
Credits: None available.
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