Adoptive T cell therapy for cancer in the clinic

Abstract

The transfusion of lymphocytes, referred to as adoptive T cell therapy, is being tested for the treatment of cancer and chronic infections. Adoptive T cell therapy has the potential to enhance antitumor immunity, augment vaccine efficacy, and limit graft-versus-host disease. This form of personalized medicine is now in various early- and late-stage clinical trials. These trials are currently testing strategies to infuse tumor-infiltrating lymphocytes, CTLs, Th cells, and Tregs. Improved molecular biology techniques have also increased enthusiasm and feasibility for testing genetically engineered T cells. The current status of the field and prospects for clinical translation are reviewed herein.

Figure 1. Schemes for adoptive transfer of autologous, vaccine-primed, in vitro–expanded T cells.

Patients are primed with tumor vaccine followed by lymphocyte harvest. Autologous T cells are harvested from peripheral blood (i) or draining lymph nodes (ii), undergo polyclonal in vitro activation and expansion, and are reinfused after lymphodepleting chemotherapy. Antigen-specific immune function is measured after the administration of booster vaccines. (iii) TILs can be isolated from resected surgical specimens and expanded in vitro for adoptive transfer after lymphodepleting chemotherapy. Most adoptive transfer therapy approaches using TILs have involved the use of IL-2 infusion following T cell transfer in order to select tumor-specific T cells.

Figure 2. Suicide T cell therapy using adoptively transferred T cells.

T cells can be engineered to express conditional suicide switches so that the T cells die when a drug is administered that activates the switch and causes apoptosis. Suicide constructs have been incorporated into allogeneic T cells that can be ablated in the event of GVHD and into autologous T cells that can be ablated in the event of toxicity or uncontrolled T cell proliferation.

Figure 3. T cells can be engineered to have retargeted specificity for tumors.

(A) Endogenous T cells express a single heterodimeric TCR. (B) Bispecific T cells are created by the introduction of genes that encode proteins that recognize antigens expressed by target tumor cells. These genes can encode natural TCRs that function in the same MHC-restricted manner as endogenous TCRs but have tumor antigen specificity. (C) Alternatively, these genes can encode chimeric tumor antigen–specific receptors, or T bodies, that target surface antigens in an MHC-independent fashion. T bodies express an extracellular ligand generally derived from an antibody and intracellular signaling modules derived from T cell–signaling proteins. LAT, linker for activation of T cells; ScFv, single chain variable fragment; ZAP70, ζ-chain–associated protein kinase 70 kDa.