Phosphatidylserine (PS) is emerging as an attractive immunotherapeutic target in the light of mounting evidence highlighting its causal link to immune suppression. We have established that exosomes derived from melanoma and ovarian tumor microenvironments express PS on their surfaces and suppress multiple activation endpoints of T cells triggered through the T cell receptor. Studies have also shown that expression of PS on the surface of many non-apoptotic cancer cells lead to immunosuppression. Recent clinical studies in melanoma patients demonstrated that exosomes that are released from patient tumors suppress T cell tumor killing and contribute to tumor progression. We have designed and synthesized a new compound, Zn-DPA)6-DP-15K (ExoBlock) that binds to phosphatidylserine with high avidity. ExoBlock was shown to consistently and significantly block the immune suppressive activity of exosomes derived from melanoma and ovarian tumor microenvironments in vitro. Based upon these findings, we predicted that ExoBlock would enhance the killing of tumor cells by T cells in tumor xenografts due to its binding to PS on the exosomes, tumor and apoptotic cells, representing a multi- pronged approach. We tested this prediction using two different human tumor xenograft models: a) the previously validated in-house developed omental tumor xenograft (OTX) model established using patient-derived ovarian tumors, and b) the recently developed and validated Xenomimetic mouse (X-mouse) model that allows us to quantify and establish the efficacy of multiple T cell-stimulating immune-based therapies pre-clinically. This model uses melanoma patient-derived tumor-specific T cells that are adoptively transferred into immunodeficient mice bearing melanoma xenografts expressing tumor neo-antigens recognized by the T cells. The therapeutic efficacy of ExoBlock was next established by significantly enhancing tumor suppression in both the OTX and X- mouse models, and was found to be comparable to anti-PD-1 therapy in X-mouse model. Together, these results have laid the foundation and rationale for our work proposed in the Phase I application. Additional toxicity and pharmacokinetic (PK) studies are proposed for ExoBlock in Aim 1. The PK studies will help to determine the optimal dose, schedule and delivery method of ExoBlock that will be tested in aim 2.
In Aim 2 ExoBlock will be tested in vivo for its therapeutic efficacy in omental tumor xenograft (OTX) model consisting of patient-derived ovarian tumor and syngeneic mouse melanoma model with B16-F10 tumor. Our rationale for using both a human and mouse tumor model is discussed in the Approach. The results of this Phase 1 study will lay the foundation for a more extensive study in a future phase 2 study that will lead to an IND and clinical trial of ExoBlock.
We have identified small (virus sized) extracellular vesicles, called exosomes present in human ovarian and melanoma tumor microenvironments that inhibit the ability of tumor specific T cells to kill tumor cells. We have identified with in vitro studies phosphatidylserine (PS) binding drug named ExoBlock that block the immune suppressive vesicles. Using animal models, we will test with in vivo studies the therapeutic efficacy of ExoBlock to enhance tumor killing by T cells. Our goal, using improved animal models for testing and more reliable measures to quantify changes in tumor burdens, is to provide convincing pre-clinical data to support a rationale for clinical trials with ovarian cancer patients and melanoma cancer patients.
