To improve CAR T cell proliferation and persistence for solid tumors, Shi et al. inserted the pre-TCR alpha (pTα) invariant domain 1A, known to stimulate a proliferative burst during thymocyte αβ T cell development, into canonical CD28-based CARs. CARs containing the pTα 1A domain (1A-CARs) resulted in greater expansion, persistence, and cytokine secretion, and enhanced survival in orthotopic RCC and GBM models, with less exhaustion. 1A-CARs showed enhanced mRNA translation via phosphorylation of YBX1, the translation master regulator. In contrast, YBX1 ablation lowered mRNA translation and cell expansion, and accelerated exhaustion.
Contributed by Katherine Turner
ABSTRACT: 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 β-selection developmental stage, which is driven by the pre-T cell receptor and its unique pTα chain. CARs harboring the pTα 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 Y-Box Binding Protein 1 (YBX1), which was required for enhanced tumor eradication. The programming of mRNA translation in T cells opens another avenue for regulating and potentiating immunotherapy.
Author Info: (1) Columbia Initiative in Cell Engineering and Therapy (CICET), Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. (2) Colum
Author Info: (1) Columbia Initiative in Cell Engineering and Therapy (CICET), Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. (2) Columbia Initiative in Cell Engineering and Therapy (CICET), Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. (3) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (4) Columbia Initiative in Cell Engineering and Therapy (CICET), Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. (5) Columbia Initiative in Cell Engineering and Therapy (CICET), Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. (6) Columbia Initiative in Cell Engineering and Therapy (CICET), Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. (7) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Cell Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (9) Columbia Initiative in Cell Engineering and Therapy (CICET), Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. (10) Orthopedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (11) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (12) Columbia Initiative in Cell Engineering and Therapy (CICET), Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. Electronic address: mws2188@cumc.columbia.edu.
