? Project 1 In brain tumors like glioblastoma (GBM), failures to develop an effective vaccine and achieve immune checkpoint inhibition have been attributed to both the remarkable immunosuppression and extraordinary antigenic intratumoral heterogeneity. A major contributor to immunosuppression in GBM is elevated regulatory T-cells (TRegs) which dramatically suppress T cell effector function and diminish the efficacy of antitumor vaccination. Efforts to deplete TRegs by targeting the interleukin-2 receptor ? (CD25) have been unsuccessful to date, due to cytotoxic effects on effector T cells, which are required to promote antitumor immunity. To overcome this hurdle, Project 1 builds novel preliminary data demonstrating the ability of a clinically available CD27 agonist antibody (?CD27) to simultaneously deplete TRegs and enhance vaccine-induced immune responses. Specifically, the Project tests the hypothesis that class I neoantigens linked to universal class II epitopes will be well-tolerated and rendered more immunogenic by the ability of the clinically available CD27 agonist antibody to deplete TRegs and simultaneously enhance vaccine-induced immune responses in patients with GBM.
Aim 1 will evaluate the safety and therapeutic potential of a neoantigen and Cytomegalovirus antigen vaccine in combination with dose-escalating ?CD27 in patients with GBM. Cumulative results will provide critical data on the feasibility and immunogenicity of neoantigen vaccination in patients with GBM to determine if a larger trial is warranted.
Aim 2 will determine if ?CD27 simultaneously depletes TRegs and increases vaccine-induced immune responses. It is expected that ?CD27 will reduce TRegs in this patient population while improving vaccine-induced CD8+ and CD4+ T cell responses. If successful, this work will develop a therapeutic strategy for patients with GBM that has enhanced efficacy by addressing the issues of host immunosuppression and intratumoral heterogeneity.
? Project 1 Glioblastoma (GBM) remains uniformly lethal with an overall survival of <21 months despite surgery, high-dose radiation, dose-limited chemotherapy, and novel therapies like tumor-treating fields. Immunotherapy induces remarkable efficacy in many cancers, but its effectiveness in GBM has been limited due to patients' remarkable immunosuppression and extraordinary tumor heterogeneity. This project develops a novel immunotherapeutic platform to address both of these critical issues.
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