Selection bias: maintaining less-differentiated T cells for adoptive immunotherapy

Abstract

The clinical application of T cell immunotherapy depends on ex vivo modification and expansion of T cells for adoptive transfer. In preclinical models, the use of a purified, naive T cell subset enhances persistence and antitumor immunity; however, the majority of clinical studies rely on modification of mixed populations of T cells that contain only a small subset of highly functional T cells with less-differentiated phenotype. In this month's issue of the JCI, Klebanoff and colleagues uncover a Fas-mediated interaction between naive T cells and antigen-experienced T cells that drives differentiation and impairs adoptive immunotherapy. Further, they show that blockade of Fas signaling enhances antitumor immunity and increases survival in a mouse model of melanoma. Their work supports a growing body of evidence that the use of naive T cells enhances the efficacy of adoptive T cell therapy and suggests a new therapeutic strategy for preserving less-differentiated T cell populations.

Figure 1. Schematic representation of the generation of engineered T cells for adoptive immunotherapy.

Unfractionated PBMCs containing T_N, T_SCM,T_CM, and T_EM cells are frequently used as starting material to generate gene-manipulated T cell products for adoptive immunotherapy in cancer patients. To preserve more immature T cell subsets, the manipulation of culture conditions by using different cocktails of cytokines or by activating or inhibiting specific pathways has been developed. In the current issue of the JCI, Klebanoff et al. suggest that the selection of T_N cells from PBMCs may represent the most effective strategy to preserve more immature T cell subsets in T cell products.