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Therapeutic Targeting PRAME with mTCRCAR T Cells in Acute Myeloid Leukemia

By September 15, 2022No Comments

Preferentially Expressed Antigen in Melanoma (PRAME) , a cancer testes antigen provides an ideal target for immunotherapy in AML. We have shown expression of PRAME in a significant subset of childhood and adult AML and lack of expression in normal hematopoiesis. Although an intracellular antigen, we developed a novel approach to target PRAME using a CAR construct encoding a targeting domain based on T cell receptor (TCR) mimic antibodies that targets the peptide:HLA complex. We used the antibody sequence from a previously designed antibody, Pr20, a TCR mimic antibody that recognizes PRAME ALY peptide in complex with HLA-A*02 and verified expression of PRAME in AML cell lines and primary AML blasts. Using the Pr20 antibody sequence, we developed CAR T cells (PRAME mTCRCAR T) to be tested against primary AML patient samples and AML cell lines that express the PRAME antigen in the context of HLA-A2 expression. In contrast to the appropriate controls, PRAME mTCRCAR T cells demonstrate target specific and HLA-mediated in vitro activity in OCI-AML2 and THP-1 cell lines, HLA-A2 cell lines expressing the PRAME antigen, and against primary AML patient samples. In vivo cell-derived xenograft models treated with PRAME mTCRCAR T cells demonstrated potent leukemia clearance and improved survival compared to unmodified T-cell controls. Furthermore, the cytolytic activity of PRAME mTCRCAR T cells was enhanced by treating the target cells with IFN-γ, which increases PRAME antigen expression. These results demonstrate the feasibility and efficacy of targeting PRAME with novel PRAME mTCRCAR T cells.