Adoptive T-cell therapy for B-cell malignancies

Abstract

The success of allogeneic hematopoietic cell transplantation (HCT) for B-cell malignancies is evidence that these tumors can be eliminated by T lymphocytes. This has encouraged the development of specific adoptive T-cell therapy, both for augmenting the anti-tumor effect of HCT and for patients not undergoing HCT. T cells that are capable of recognizing antigens expressed on malignant B cells may be recruited from the endogenous repertoire or engineered to express tumor-targeting receptors. Critical insights into the qualities of T cells that enable their persistence and function in vivo have been derived, and obstacles to effective T-cell-mediated tumor eradication are being elucidated. These advances provide the tools to translate adoptive T-cell transfer into reliable clinical therapies.

Figure 1. Expression of minor H antigens on tumor cells and epithelium dictate GVHD and GVT activity mediated by donor T cells

Minor H antigens that are selectively expressed on tumor cells but not on epithelium can serve as targets for a selective GVT response in the absence of GVHD. T cells specific for minor H antigens expressed on both tumor and epithelium can mediate both a GVT effect and GVHD, those specific for minor H antigens on tumor but not epithelium mediate a selective GVT response, while those specific for minor H antigens on epithelium but not on tumor only mediate GVHD. GVHD: Graft-versus-host disease; GVT: Graft-versus-tumor.

Figure 2. Gene transfer can retarget primary T cells to recognize tumor cells

Schematic demonstration of the engineering of bispecific T cells by inserting the α- and β-genes of a TCR specific for a tumor-associated antigen, or a gene encoding a CAR constructed of a single-chain antibody fragment fused to TCR signaling domains. CAR: Chimeric antigen receptor; TCR: T-cell receptor.