Optimizing the manufacturing and antitumour response of CAR T therapy

Adoptive transfer of naturally occurring or genetically engineered T cells is an effective treatment for certain haematological malignancies, such as non-Hodgkin lymphoma and acute lymphoblastic leukaemia, but still faces challenges in treating solid tumours. The phenotype of the final T cell product substantially affects in vivo antitumour efficacy, and various strategies have been developed to manipulate T cell phenotype during chimeric antigen receptor (CAR)-expressing T cell manufacturing to improve in vivo responses after T cell infusion. In this Review, we provide an overview of specific T cell attributes that influence the performance of adoptive T cell transfers, including memory T cell population, CD4:CD8 composition and CD4 subsets. Moreover, we discuss how different T cell subsets interact with and are affected by the immunosuppressive tumour microenvironment, including the role of preconditioning in CAR T therapies. We then review strategies to control T cell phenotype and antitumour performance after infusion through manipulation of the three signals for T cell activation and downstream signalling pathways during manufacturing. We finish by discussing developments in rapid manufacturing of CAR T cell products.