Project Summary/Abstract The goal of this collaboration between the Lim/UCSF and June/UPenn IOTN centers is to develop a novel approach to autonomously and selectively drive proliferation of CAR T cells within a solid tumor. Current clinical data indicates that strong proliferation is critical for therapeutic success of adoptively transferred T cells1,2. In solid tumors this is a particularly acute challenge as tumor cells are surrounded by an immunosuppressive microenvironment that presents multiple barriers to T cell expansion and activity, including suppressive regulatory T cells that act as sinks for pro-proliferation cytokines3, as well as other suppressor cells and factors that promote terminal T cell differentiation into an exhausted state4,5. To address these problems, we will combine the expertise of our two groups: the Garcia Lab (June/UPenn center) has expertise in engineering orthogonal cytokine/receptor systems, while the Lim Lab (Lim/UCSF center) has expertise in engineering synthetic helper cells that can autonomously recognize and remodel the tumor microenvironment in a targeted way using synthetic paracrine cytokine circuits. In this collaboration, we propose to engineer synthetic helper cells that autonomously produce orthogonal IL-26 in tumors, thereby selectively driving CAR T cell expansion locally. This collaboration merges approaches from both centers in a synergistic way. If successful, this approach will yield a way to promote CAR T cell expansion in tumors more effectively, selectively and autonomously than approaches within the original individual center aims. Our specific aims are to: Aim 1. Engineer synthetic helper T cells that deliver ortho-IL2 to the tumor micro-environment Aim 1.1: Engineer mouse ortho-IL-2 helper/killer cell system; test in vitro and in syngeneic tumor models Aim 1.2: Engineer human ortho-IL-2 helper/killer cell system; test in vitro and in NSG xenograft tumor models Aim 2: Modulate orthogonal IL-2 receptor signaling to improve and tune cell responses to ortho-IL2. Systematically alter the signaling domains in the ortho-IL-2 receptor intracellular domain to identify and deploy variants that increase T cell proliferation and/or minimize exhaustion.

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