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Home / Research / Seed Grant Program / Seed Grant Recipients / Greg Allen, MD, PhD

Greg Allen, MD, PhD

Greg Allen, MD, PhD
Greg Allen, MD, PhD Assistant Professor
Department of Medicine, Hematology and Oncology
University of California, San Francisco
San Francisco, CA

Developing next-generation cellular therapies to remodel immunosuppressive pancreatic tumor micro-environments.

Overview

Aim: Therapy

Immunotherapies have been a revolutionary treatment for many tumors, but their promise remains unfulfilled in pancreatic cancer. The immune-suppressive nature of the pancreatic tumor microenvironment (TME) has proven refractory to check-point inhibitors, bispecific antibodies, and cellular therapies. Although many powerful agents have been identified that can over-write this suppressive environment their therapeutic potential is limited due to systemic toxicities. For example, high dose regimes of the cytokine IL-2 can drive tumor regression but also elicits severe toxicity because cytokine acts on healthy bystander tissue.

Here we propose a new treatment paradigm, where immune cells are genetically engineered to locally deliver therapeutic agents directly into tumors – bypassing systemic toxicity. In our preliminary work we have utilized a novel cell-sensing receptor platform (synNotch) to engineer primary T cells to sense a tumor antigen of interest, and in response, to locally express a genetically encoded cytokine payload only within the targeted tumor. We found that engineering chimeric antigen receptor (CAR) T cells with tools for cell autonomous, but tumor triggered, cytokine production can overcome previously unsurmountable barriers to CAR T cell infiltration and activation.

In this project we will develop and apply tools that allow CAR T cells to deliver multiple cytokines precisely and locally to tumors. We will combine key effector cytokines to both drive CAR T cell infiltration and activity as well as locally reprogram the TME and stimulate endogenous immunity. This reversal of the suppressive TME will allow for a cellular therapy that can overcome critical unmet challenges in target antigen heterogeneity and CAR T cell persistence. In our work we will couple our cellular reprograming of the TME with thorough high-dimensional analysis to generate mechanistic insight, with a final goal of the development of a next-generation cellular therapy for future clinical translation.

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