Cellular networks controlling T cell persistence in adoptive cell therapy

The antitumour activity of endogenous or adoptively transferred tumour-specific T cells is highly dependent on their differentiation status. It is now apparent that less differentiated T cells compared with fully differentiated effector T cells have better antitumour therapeutic effects owing to their enhanced capacity to expand and their long-term persistence. In patients with cancer, the presence of endogenous or adoptively transferred T cells with stem-like memory or precursor phenotype correlates with improved therapeutic outcomes. Advances in our understanding of T cell differentiation states at the epigenetic and transcriptional levels have led to the development of novel methods to generate tumour-specific T cells — namely, chimeric antigen receptor T cells — that are more persistent and resistant to the development of dysfunction. These include the use of novel culture methods before infusion, modulation of transcriptional, metabolic and/or epigenetic programming, and strategies that fine-tune antigen receptor signalling. This Review discusses existing barriers and strategies to overcome them for successful T cell expansion and persistence in the context of adoptive T cell immunotherapy for solid cancers. Successful adoptive cell therapy for cancer depends on the expansion and persistence of tumour-specific T cells with stem-like memory or precursor characteristics. Here, the authors describe approaches to generate these cells by in vitro culture methods, by modulating transcriptional, metabolic and/or epigenetic programming, and by fine-tuning antigen receptor signalling.