pTa enhances mRNA translation and potentiates CAR T cells for solid tumor eradication [eCLIP-seq]

Current chimeric antigen receptor (CAR) therapies are effective against a range of hematological malignancies and autoimmune disorders but have shown limited activity against solid tumors. In searching for effective means to enhance the functional persistence and potency of CAR T cells, we explored the potential of integrating pre-T cell features into canonical CD28-based CARs. Thymocytes undergo a proliferation burst during the ß-selection developmental stage, which is driven by the pre-T cell receptor and its unique pTa chain. CARs harboring the pTa 1A domain imparted greater expansion, cytokine production, and in vivo persistence to T cells, accompanied by lowered exhaustion and greater long-term tumor control in multiple liquid and solid tumor models. CARs incorporating the 1A domain showed sustained phosphorylation of the mRNA translation master regulator YBX1, which was required for enhanced tumor eradication. The programing of mRNA translation in T cells opens another avenue for regulating and potentiating immunotherapy. Overall design: 19-28z and 19-28z-1A CAR T cells 48hour post NALM6 stimulation