The therapeutic potential of T-cell immunotherapy is limited by major immunotoxicities such as graft-versus-host disease (GVHD), immune checkpoint blocker (ICB) colitis and the loss of persistence, and exhaustion of transferred T cells. This proposal aims to address these problems. It blends hypothesis-driven studies that are informed by unbiased discovery-based explorations. Most advances in the field are focused on the sensor and effector arms of the problem, namely the immune cells. Herein we will take a distinct approach; focus on both immune target cells and on effector T cells. Thus, the goals of the proposal are two themes that tackle the two ends of the immunotherapy: the targets and...

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The therapeutic potential of T-cell immunotherapy is limited by major immunotoxicities such as graft-versus-host disease (GVHD), immune checkpoint blocker (ICB) colitis and the loss of persistence, and exhaustion of transferred T cells. This proposal aims to address these problems. It blends hypothesis-driven studies that are informed by unbiased discovery-based explorations. Most advances in the field are focused on the sensor and effector arms of the problem, namely the immune cells. Herein we will take a distinct approach; focus on both immune target cells and on effector T cells. Thus, the goals of the proposal are two themes that tackle the two ends of the immunotherapy: the targets and the effectors. The first theme has 4 objectives. The first objective will explore the role of target cell specific metabolic adaptations in promoting cellular resilience and ferroptosis (sensitivity) to T cells. The second objective will analyze the lasting effects the effector T cells have on immune targets through epigenetic reprogramming. The third objective will explore the cause of microbiome changes following immunotherapy and determine whether those changes amplify/regulate the severity of the immunotoxicities. The fourth objective is to develop a proof-of-concept clinical trial in patients from the above insights in patients receiving ICB therapy or allo-HCT. We anticipate that these objectives will collectively take 30-60 months for completion. In theme 2, we will focus on T-cells. This will build on our exciting observations that disruption of the nuclear structure in T-cells by deleting WAPL, will disentangle exhaustion from other T-cell responses (complete in 48-60 months). Leadership goals: Because I am being recruited as the Director for the Dan L Duncan Cancer Center, I would also like to add a brief statement goal for this role. I aim to build on its rich legacy, to make it a world class translational powerhouse in cancer care.

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