T-cell adoptive therapy of tumors: Mechanisms of improved therapeutic performance

The T cells of many cancer patients are naturally sensitized to tumor-assoc iated antigens (Ag), or they can readily be sensitized with vaccine maneuve rs. In melanoma patients, the adoptive transfer of such T cells can often b e causally linked to the objective regression of established tumors. So far , few patients have shown sustained clinical benefit from such therapy, but preclinical mouse studies have now clearly delineated the hurdles that mus t be overcome to render T-cell-based antitumor therapy effective. Contrary to earlier expectations, it is now established that remarkably potent CD4() and CD8(+) pre-effector T cells are naturally sensitized even in mice bea ring progressive, weakly immunogenic tumors. However, such T cells often di splay signal transduction impairments as a consequence of the tumor environ ment, which limit their acquisition of optimal effector function. Extracorp orealization and culture of these tumor-sensitized T cells with appropriate activation stimuli not only restores normal signal transduction, but also confers resolute effector activity that can often sustain tumor rejection u pon reinfusion. In mouse studies, the L-selectin(low) fraction of T cells i n tumor-draining lymph nodes (TDLN) constitutes the potent pre-effector pop ulation and comprises both CD4(+) and helper-independent CD8(+) T cells. Ap propriate in vitro activation confers an apparently unrestricted traffickin g capacity to this fraction, and even the ability to proliferate within the tumor bed, leading to unprecedented tumor rejection at anatomic sites (e.g ., subcutaneous and intracranial) that were historically refractory to such treatment. Such results underscore the surprising capacity of appropriatel y activated effector T cells to withstand the immunosuppressive, tolerogeni c, and apoptotic influences of the typical tumor environment. Given the inc reasingly appreciated and critical communications between T cells and host Ag-presenting cells (APC), which cross-present tumor Ag, it is likely that dendritic cell-based vaccine maneuvers that promote sensitization of T1-com mitted L-selectin(low) antitumor T cells will play an increasingly importan t role in adoptive therapy strategies.