Project 1: Targeting immunotherapy-induced resistance with DC vaccination and PD-1/CSF-1R inhibition

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PROJECT SUMMARY/ABSTRACT – Project 1 The lack of effective treatments for glioblastoma (GBM) patients remains a significant health problem and highlights the need for novel and innovative approaches. Immunotherapy is an appealing strategy because of the potential ability for immune cells to traffic to and destroy infiltrating tumor cells in the brain. For the past 15 years, our group and others have been testing active vaccination strategies, such as dendritic cells (DC) pulsed with tumor lysate, to induce antitumor immunity in glioblastoma patients. From the interim results of the clinical trial we initiated in our current SPORE funding period, we found that in addition to inducing T-cell infiltration into brain tumors, DC vaccination + anti-PD1 blockade may also create a pro-inflammatory environment within the tumor that induces the immigration of immunosuppressive myeloid cells (TIM). These cells are phenotypically similar to the myeloid cells that dominantly attenuate the T-cell response to chronic viral infections, and may counteract the effective anti-tumor T-cell responses induced by DC vaccination within the tumor microenvironment. Therapies that target myeloid cells within the tumor microenvironment represent a promising new strategy. As such, inhibition of these myeloid cells using a CSF-1R inhibitor, in conjunction with autologous tumor lysate-pulsed DC vaccination (ATL-DC) and PD-1 mAb blockade, resulted in significantly prolonged survival in tumor-bearing animals with large, well-established intracranial (i.c.) gliomas. Our hypothesis is that myeloid cells mediate adaptive immune resistance in response to T cell activation induced by immunotherapy. In this SPORE Project renewal, we have planned a series of novel pre-clinical studies to re- polarize myeloid cells, to optimize how the timing and sequence of immunotherapy can influence ant-tumor immunity, and a new clinical trial to test the first-in-human combination of a new brain penetrant CSF-1R inhibitor (CSF-1Ri; PLX3397, Daiichi-Sankyo) with DC vaccination and PD-1 mAb blockade (Pembrolizumab, Merck) in patients with newly diagnosed GBM. A better understanding of the biology of these cellular interactions will provide insight into more effective ways to induce therapeutic anti-tumor immune responses for this deadly type of brain tumor. These studies span the continuum of translational research in brain tumor immunotherapy, and will likely provided informative new insights for the development of new, rational immune-based strategies for brain tumor patients.