Adoptive immunotherapy for cancer: building on success

Abstract

Adoptive cell transfer (ACT) of tumour-specific T cells to a lymphodepleted host mediates objective clinical responses in a substantial percentage of patients with metastatic solid tumours. CD4⁺ forkhead box P3 (FOXP3)⁺ regulatory T (T_Reg) cells are interleukin-2 (IL-2)-dependent negative immunoregulators of immune responses to self- and non-self-antigens in vivo. They might suppress antitumour responses, contributing to the poor clinical responses in patients with cancer (especially those who receive immunotherapy in non-lymphodepleting settings). Homeostatic cytokines such as IL-7 and IL-15 increase CD8⁺ T-cell functions and are required for their maintenance and memory CD8⁺ T-cell generation. Competing immune cells, including T cells, B cells and natural killer (NK) cells, might function as sinks for these cytokines, attenuating antitumour responses in non-lymphodepleting settings. Lymphodepleting regimens including systemic chemotherapy and total body irradiation can have an impact on antigen-presenting cell (APC) function and numbers. Although these regimens might deplete the absolute number of APCs, they can also promote the functional maturation of these cells. Preclinical mouse models of ACT therapy have elucidated the phenotype and the functional characteristics of CD8⁺ T cells associated with superior antitumour treatment. These attributes include lymph-node homing capacity, cytokine secretion, responsiveness to homeostatic signals, replicative history and proliferative potential. In patients, T-cell engraftment after ACT is associated with expression of the co-stimulatory molecules CD28 and CD27 and IL-7 receptor α-chain and it might indicate a selective survival of less-differentiated T cells. Persistence of adoptively transferred T cells correlates with successful antitumour responses and is associated with T-cell proliferative capacity as a function of telomere length. T-cell receptor (TCR) transduction of naive T cells or haematopoietic stem cells can be used to generate de novo, less-differentiated, central-memory-like tumour-specific CD8⁺ T cells for ACT. More robust lymphodepleting preconditioning regimens might augment the survival and antitumour function of adoptively transferred T cells. Criteria used for selection of T cells for ACT, interferon-γ release and cytolytic function, might be expanded to include TCR affinity, phenotypic analyses, alternative cytokine production (such as IL-2) and the measurement of telomere length.