Adoptive transfer of virus-specific and tumor-specific T cell immunity

Abstract

The adoptive transfer of T cells isolated or engineered to have specificity for diseased cells represents an ideal approach for the targeted therapy of human viral and malignant diseases. The therapeutic potential of adoptive T cell therapy for infections and cancer was demonstrated in rodent models long ago, but the task of translating this approach into an effective clinical therapy has not been easy. Carefully designed clinical trials have evaluated the transfer of antigen-specific T cells in humans, and provided insight into the barriers to efficacy and strategies to improve T cell therapy. The importance of altering the host environment to facilitate persistence and function of transferred T cells and intrinsic properties of T cells that are selected or engineered for therapy in determining their fate in vivo are key issues that have recently emerged and are informing the design of the next generation of clinical trials.

Figure 1. Glucocorticoids exert negative effects on adoptively transferred T cells through both nongenomic and genomic mechanisms

The non ligated glucocorticoid receptor (GR) is associated with the T cell receptor signaling complexes containing Fyn and Lck. Immediately upon binding of the GR to glucocorticoid (GC), these multiprotein complexes are disrupted leading to failure of downstream signaling after engagement of the TCR by antigen. Binding of GC to the GR in the cytoplasm also leads to translocation of the bound receptor to the nucleus and regulation of a number of glucocorticoid responsive genes, including repression of proinflammatory genes such as IL-2, and activation of immunosuppressive genes such as MAPK phosphatase-1, and interleukin 10.

Figure 2. Fate of adoptively transferred CD8⁺ effector T cells derived from distinct T cell subsets

Effector T cells (T_E) can be derived from naïve (T_N), central memory (T_CM), and effector memory (T_EM) subsets and express a CD62L^-, CCR7^-, granzyme B^hi, and perforin^hi phenotype. Despite the similar phenotype at the time of adoptive transfer, T cells derived from T_EM precursors die rapidly after cell transfer and do not establish persistent T cell memory. T cells derived from T_CM precursors survive long term in vivo and revert to both CD62L⁺ and CD62L^- memory cells. A subset of the transferred cells that reexpress CD62L and CCR-7 reside in lymph nodes, downregulate expression of granzyme B and perforin and are capable of responding to antigen challenge. The fate of T_E derived from naïve precursors in vitro has not yet been definitively established in a large animal model.

Figure 3. Engineering tumor-reactive effector T cells by insertion of genes that encode tumor-specific T cell receptors or chimeric antigen receptors into central memory T cells

The superior persistence of effector T cells derived from virus-specific T_CM suggests that this subset of T cells should be isolated based on their expression of CD45RO and CD62L for insertion of genes that encode TCR or chimeric antigen receptors (CAR) to target molecules on tumor cells. After insertion of the tumor-targeting receptors, the engineered T cells could be expanded in vitro and despite differentiating to cytolytic effector cells will retain the intrinsic capacity to persist in vivo after adoptive transfer and revert to the memory pool.