Lamture G, Baer A, Fischer JW, et al. TCR-Independent Activation in Presence of a Src-Family Kinase Inhibitor Improves CAR-T Cell Product Attributes. Journal of Immunotherapy. 2022; 45 (3): 139 (doi: 10.1097/CJI.0000000000000402).
Manufacturing chimeric antigen receptor (CAR) T cells without engaging the T-cell receptor (TCR), but in the presence of an Src-kinase inhibitor (SKI), avoids some of the shortcomings associated with TCR-dependent (TCRD) activation. Researchers discovered this when comparing the novel approach with the established technique. Compared with TCRD activation, TCR-independent (TCRI) activation in the presence of an SKI significantly improved CAR T cell expansion. Greater volumes of naive and central memory cells were generated, along with lower volumes of effector cells in the CAR T cell product, suggesting better persistence and improved in vivo functionality. TCRI also reduced markers of T-cell activation, differentiation, and exhaustion — which can affect CAR T cell product quality and in vivo potency, if allowed to go unchecked — more effectively than TCRD. Further study is warranted, the investigators note, "to better understand mechanisms for improvement of these product quality attributes, which may help develop strategies to improve CAR T cell manufacturing, safety, efficacy and reduce manufacturing failures."