Adoptive therapy with CD8(+) T cells: it may get by with a little help from its friends.

The clinical goal of immunotherapy has traditionally been to provide either active or passive immunity against an infection or malignancy. In the active approach, antigen is administered (with or without some form of adjuvant) to initiate the generation within the host of a protective or therapeutic immune response. By contrast, in adoptive (or passive) cellular immunotherapy, the specific effectors of immunity are directly administered, bypassing the obstacles in the host that might prevent the generation of an effective response in vivo. Adoptive immunotherapy with CD8+ T cells permits the use of large numbers of effector T cell clones or lines of defined specificity and function, but has the disadvantage of requiring significant effort and technologic skill to isolate and expand such CTLs in vitro to the numbers needed to establish an effective in vivo response and successfully control the infection or tumor. Adoptive T cell therapy is currently being investigated as an approach to treat both infectious (e.g., cytomegalovirus [CMV], HIV, and Epstein-Barr virus [EBV]) and malignant (e.g., melanoma and leukemia) diseases in humans (1–6). Preclinical and clinical studies have elucidated several issues that need to be addressed to improve the likelihood of success — including choosing appropriate target antigens, optimizing the methods for generating functional T cells in vitro, and providing requisite cytokines and/or proinflammatory signals to support the survival and effector functions of the T cells after infusion. In this issue of the JCI, Tuma and colleagues have used a murine model of immunity against the intracellular bacterium Listeria monocytogenes to evaluate a potential obstacle to T cell therapy, and demonstrate the utility of providing an inflammatory stimulus (CD40 activation) to rescue otherwise ineffective adoptively transferred CD8+ T cells (7). Their provocative findings are discussed below among the strategies currently being investigated to overcome current limitations of adoptive T cell therapy.