Redirecting the immune response: role of adoptive T cell therapy

Abstract

Adoptive T cell therapy is aimed at overcoming constraints of the endogenous immune response. In patients with malignancies, this approach is based on the possibility of administering sufficient numbers of tumor-reactive lymphocytes under conditions in which they will promote a therapeutic response. Although this strategy is potentially applicable to a vast number of malignancies, its efficacy, to date, has been limited. This is likely related to several factors including an insufficient persistence and reactivation of infused cells, insufficient tumor infiltration, and the presence of an immunosuppressive environment. Here, we review the importance of pretransplantation host conditioning and posttransplantation strategies that have been shown to contribute to the therapeutic efficacy of infused T lymphocytes.

FIG. 1.

Factors implicated in the success of adoptive T cell therapy (ACT) against tumors. Shown are some of the important steps and critical questions in ACT. It is initially important to determine whether naive (T_N), central memory (T_CM), or effector (T_E) T cells are optimal for transfer and whether it is best to isolate them from peripheral blood or from the tumor itself (1). To obtain the most “fit” tumor-reactive T cells, a tumor-specific chimeric antigen receptor (CAR) or T cell receptor (TCR) can be introduced by retrovirus- or lentivirus-mediated technology after ex vivo stimulation and/or expansion (2). These tumor-specific lymphocytes are then infused into tumor-bearing individuals preconditioned to favor the survival/persistence and activity of the transferred cells (3 and 4). Posttransplantation treatment of the patients with cytokines, stimulatory or antagonist antibodies, and vaccination further favors the in vivo expansion of tumor-specific lymphocytes. CTLA, cytotoxic T lymphocyte antigen; IL, interleukin; TGFβ, transforming growth factor β; Treg, regulatory T cells. Color images available online at www.liebertonline.com/hum.