The Impact of Gene Therapy on T Cell Function in Cancer

Abstract

Studies of signal transduction by T cells are slowly identifying the intracellular messengers that must be generated for full T cell activation to take place. The recent, convincing identification of several tumor-associated antigens (TAA) has transformed our task into trying to define the mechanisms that underlie the failure of T cells to destroy antigenic tumor cells. Although there are a variety of hypotheses that explain why tumors grow progressively, even if they are antigenic, recent evidence suggests that T cells from tumor-bearing patients exhibit abnormalities in signal transduction that render them unable to respond to appropriate activation signals, even following proper stimulation. Gene therapy with interleukin-2 (IL-2)-secreting tumor cells in an animal model has been effective in preventing the onset of these signaling defects. Discovery of the molecular mechanisms by which such cytokine-secreting tumor cells induce immune responses and how they may best be applied clinically may provide clearer indications of the directions to pursue to alter the balance between the T cell and the tumor cell in the patient's favor. Gene therapy using tumor cells genetically engineered to express diverse immunostimulatory products is a promising technique for stimulating anti-tumor responses. A potential pitfall in some cancer patients, however, is that T cells, the major targets of stimulation by vaccines, respond abnormally to activation signals, which result in a state of immune suppression. Recently, there has been progress in defining the nature of the signaling defects that prevent the development of effector activity by these T cells. The demonstration that gene therapy with interleukin-2 (IL-2) secreting tumor cells was effective in preventing the onset of these signaling defects suggests that this approach may be effective as adjuvant therapy to prevent disease recurrence following standard treatment.