Chimeric antigen receptor (CAR) T cells, an immunotherapy that has been successful in treating blood cancers, has had limited efficacy in solid tumors including in pancreatic cancer. Greg Allen, MD, PhD, an Assistant Professor in the Department of Medicine at University of California, San Francisco, believes that CAR T cells offer tremendous potential for the treatment of PDAC and his 2023 Hirshberg Foundation Seed Grant Award project, Developing next-generation therapies to remodel immunosuppressive pancreatic tumor microenvironments focuses on engineering CAR T cells to be effective in the unique tumor microenvironment of pancreatic tumors.
CAR T cell therapy harvests a patient’s own T cells, a type of immune cell, engineers them to express a receptor to identify tumor cells, activate the T cells, and lead to cancer cell death. Pancreatic cancer has been resistant to immunotherapy approaches, in part, because of the immunosuppressive nature of the tumor microenvironment and this suppression is extended to CAR T cell therapy. One way to counter this immune suppression is the delivery of immune cell modulating signals called cytokines to the patient. Cytokines such as interleukin-2 (IL-2) stimulate T cells and potentially reverse aspects of immune suppression. Systemic IL-2 treatment has been shown to work for some cancers such as melanoma, but it also causes severe adverse events, and its use has been limited. It is thought that cytokines delivered locally to the tumor could allow for immunotherapy to work while limiting severe side effects observed when it is delivered systemically or throughout the whole body.
Dr. Allen’s Seed Grant project aims to engineer T cells to express both chimeric antigen receptors (CARs) that identify tumor specific proteins as well as cytokines, such as IL-2, that are designed to be expressed only in the tumor microenvironment. Dr. Allen’s 2022 publication in the journal Science, Synthetic cytokine circuits that drive T cells into immune excluded tumors demonstrated that this approach could increase T cell infiltration into the tumor microenvironment and clear pancreatic tumors in preclinical models. He is now extending this work to evaluate if multiple cytokines can be expressed by these engineered CAR T cells and what cytokines, in combination with IL-2, may work best for pancreatic tumors in preclinical models. His work has identified a T cell stimulating cytokine that more effectively slowed or reversed the growth of pancreatic tumors in preclinical models than IL-2 or even in combination with IL-2. Ongoing work includes profiling the tumor microenvironment in these preclinical models using multiple complementary techniques to understand how treatment remodels the tumor microenvironment to support an anti-tumor immune response.
The goal of Dr. Allen’s work is to translate this therapy into an academic phase I clinical trial for pancreatic cancer patients. The first step for any clinical trial is the preclinical proof concept and mechanistic studies such as those currently being accomplished in Dr. Allen’s lab. Dr. Allen will be sharing an update on this work in October at the Hirshberg Foundation-UCLA Research Forum on Pancreatic Cancer Research.
