Sunday, November 24, 2024
11/24/2024
Project Summary Adoptive transfer of T cells genetically engineered to express CD19-specific chimeric antigen receptors (CARs) have achieved tremendous clinical success in treating patients with refractory and relapsed B-cell leukemia. Since the approval of CD19 CAR-T cells in 2017 by the US Food and Drug Administration (FDA), research in the field has grown exponentially, ranging from therapies for melanoma and solid tumors, induction of transplantation tolerance to treatment of autoimmune diseases. Despite these successes, the treatment also has severe toxicities due to the excessive immune responses. Cytokine release syndrome (CRS), manifesting as serum cytokine over-production, fever, hypotension, and multiple organ dysfunction/failure, is one of the major side effects that can cause permanent damage to patients if left without proper clinical intervention. While clinical protocols have been developed to mitigate the pathophysiology of CRS in clinic, the underlying mechanisms responsible for the excessive cytokine secretion remains not fully understood. One of the major hurdles is the lack of preclinical models that can fully recapitulate the CAR-T cell-mediated immune interactions. Hematopoietic humanized (hu) mouse models are a powerful platform to bridge the gap between preclinical studies and clinical CRS, and have been instrumental in developing novel therapies to mitigate CRS- medicated toxicities. However, recreating the complex human immune system in these mice is challenging, as they don’t have a human thymus, the primary lymphoid organ responsible for the generation and selection of T cells. Although the endogenous mouse thymus can provide limited support for human T cell development, human T cells generated in mouse thymus cannot properly engage with other human immune cells to regulate effective immune responses. We have recently developed a tissue-engineering method to generate human thymus from inducible pluripotent stem cells (iPSCs). iPSC-derived human thymus can support the de novo generation of a functional human T cell compartment in hu mice that can mediate both cellular and humoral immune responses. Based on these findings, we hypothesize that hu mice engrafted with iPSC-thymus can recapitulate the complex interactions between the human immune system and cancer cells under CAR-T therapy, and serve as a powerful model to study CRS pathophysiologies for the discovery of novel therapies. In this exploratory project, we are going to establish and characterize a CD19 CAR-T/B-lymphoblastic cancer model with the iPSC-thymus engrafted hu mice to recapitulate CRS and its associated toxicities. If successful, the project will have broad impacts in the field of immunotherapy.
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