Adoptive T-cell therapy involves ex vivo expansion of tumor-specific T cells to large numbers and the infusion of those T cells into patients. Cells are expanded in vitro by various methods, such as treatment with IL-2, anti-CD3 antibodies, and allogeneic antigen-presenting cells to provide a co-stimulatory signal. Adoptive T-cell therapy is made more effective when the patient is immunosuppressed before treatment and IL-2 is then administered systemically. Another approach that has excited much interest is the use of retroviral vectors to transfer tumor-specific T-cell receptor (TCR) genes into patients’ T cells before reinfusion. This can have long-lasting effects as a result of the ability of T cells to become memory cells, and there is no requirement for histocompatibility because the transfused cells are derived from the patient.
Another form of adoptive immunotherapy also uses retroviruses to introduce genes into a patient’s T cells, but involves expressing a novel type of receptor, known as a chimeric antigen receptor (CAR). CARs are fusion receptors that contain extracellular antigen-specific domains fused to intracellular domains that provide signals for activation and co-stimulation. These receptors are introduced into T cells via retroviral vectors to produce so-called CAR T cells. This approach differs from conventional adoptive T-cell therapies as the use of a CAR allows the T cell’s target specificity to be almost any molecule recognizable by an antibody rather than just peptide:MHC complexes. Recently this approach was used to target CD19 as a tumor rejection antigen in treating acute lymphocytic leukemia (ALL), an aggressive cancer of transformed B cells (Fig. 16.18). The CAR used in this case had an extracellular domain of an antibody that recognizes human CD19. The intracellular domain had three ITAMs from the ζ chain of the T-cell receptor CD3 complex (see Chapter 7) fused with a co-stimulation domain from 4-1BB, a member of the TNF receptor superfamily. These CART-19 transduced T cells were expanded in vitro and transferred into a patient. The results of this case combined with others have demonstrated that CD8 T cells expressing CART-19 (see Fig. 16.18) are effective at achieving complete clinical remissions in many patients with ALL. This approach is not without its side-effects, however, as it also eliminates normal B cells in patients and they therefore require treatment with IVIG.