336 Alloimmune defense receptor with genetic ablation of adhesion ligand CD58 promotes functional persistence of allogeneic cell therapies without conditioning chemotherapy

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Background Clinical administration of chimeric antigen receptor (CAR) NK cell and CAR T-cell therapies require conditioning chemotherapy (CCT) to deplete the host immune system, maximize access to homeostatic cytokines, and promote cell expansion and functional persistence. However, CCT also elicits pan-immune cell cytopenia, increases susceptibility to infection and malignancy, and requires patient hospitalization and administration of therapy in costly tertiary healthcare settings. The administration of off-the-shelf CAR NK cell and CAR T-cell therapies to patients without requiring CCT has the potential to significantly reduce toxicities and cost of care, and, importantly, extend patient reach by enabling treatment in primary or outpatient community healthcare settings. Methods We have developed a unique approach to promote the functional persistence of cell therapy in the absence of CCT through the cooperative action of a novel alloimmune defense receptor (ADR), which eliminates 41BB+ alloreactive immune cells, and the genetic disruption of CD58 (CD58KO), a unidirectional synapse-stabilizing ligand which is required for effector:target cell association. Results In a mixed lymphocyte reaction containing target cells, ADR-armed CD58KO iPSC-derived CAR T (CAR iT) cells were resistant to immune cell-mediated depletion and maintained complete functional activity against target cells. Importantly, CAR iT cells selectively eliminated activated 41BB+ alloreactive immune cells, as naïve and non-alloreactive lymphocytes were spared. Moreover, functional activity against target cells was maintained upon serial restimulation with either target cells or HLA-mismatched PBMCs, indicating durability of CAR iT cell function. In a xenograft model of disseminated disease, CAR iT cells uniquely maintained effector function and resulted in durable elimination of target cells in the presence of an allogeneic T-cell system. Conclusions Collectively, we demonstrate the potential of off-the-shelf cell therapy, through the novel combination of ADR and CD58KO, to elicit a robust cytotoxic response against diseased cells in the presence of an intact endogenous immune compartment. The effective use of cell-based immunotherapies without requiring administration of CCT to patients facilitates broad clinical application across multiple lines of therapy, including in combination with standard-of-care agents that are used for treatment of patients with newly-diagnosed disease.

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