? 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.
|Dobrikov, Mikhail I; Dobrikova, Elena Y; Gromeier, Matthias (2018) Ribosomal RACK1:Protein Kinase C ?II Phosphorylates Eukaryotic Initiation Factor 4G1 at S1093 To Modulate Cap-Dependent and -Independent Translation Initiation. Mol Cell Biol 38:|
|Desjardins, Annick; Gromeier, Matthias; Herndon 2nd, James E et al. (2018) Recurrent Glioblastoma Treated with Recombinant Poliovirus. N Engl J Med 379:150-161|
|Gromeier, Matthias; Nair, Smita K (2018) Recombinant Poliovirus for Cancer Immunotherapy. Annu Rev Med 69:289-299|
|Lin, Jiaxing; Gresham, Jeremy; Wang, Tongrong et al. (2018) bcSeq: an R package for fast sequence mapping in high-throughput shRNA and CRISPR screens. Bioinformatics 34:3581-3583|
|Swartz, Adam M; Reap, Elizabeth; Norberg, Pamela et al. (2018) A simple and enzyme-free method for processing infiltrating lymphocytes from small mouse tumors for ELISpot analysis. J Immunol Methods 459:90-93|
|Chong, Mengyang; Yin, Tao; Chen, Rui et al. (2018) CD36 initiates the secretory phenotype during the establishment of cellular senescence. EMBO Rep 19:|
|Thompson, Eric M; Brown, Michael; Dobrikova, Elena et al. (2018) Poliovirus Receptor (CD155) Expression in Pediatric Brain Tumors Mediates Oncolysis of Medulloblastoma and Pleomorphic Xanthoastrocytoma. J Neuropathol Exp Neurol 77:696-702|
|Woroniecka, Karolina; Chongsathidkiet, Pakawat; Rhodin, Kristen et al. (2018) T-Cell Exhaustion Signatures Vary with Tumor Type and Are Severe in Glioblastoma. Clin Cancer Res 24:4175-4186|
|Woroniecka, Karolina I; Rhodin, Kristen E; Chongsathidkiet, Pakawat et al. (2018) T-cell Dysfunction in Glioblastoma: Applying a New Framework. Clin Cancer Res 24:3792-3802|
|Zhao, Lintao; He, Ran; Long, Haixia et al. (2018) Late-stage tumors induce anemia and immunosuppressive extramedullary erythroid progenitor cells. Nat Med 24:1536-1544|
Showing the most recent 10 out of 39 publications