Biologic response modifiers in acute lymphoblastic leukemia.

ABSTRACT

Despite the presence of tumor antigens, the paucity of clinically significant T-cell mediated immune responses against human tumors is striking. This may, in part, be because of the inability of cancer cells to function as efficient antigen-presenting cells. For full activation, T cells must receive two signals delivered by antigen-presenting cells. The first is antigen-specific and is delivered by presentation of antigenic peptide by the major histocompatibility complex molecules to the T-cell receptor. This signal, although necessary, is in itself insufficient to mediate T-cell activation, cytokine release, and subsequent T-cell proliferation and function. For full T-cell activation, T cells require delivery of a secondary, costimulatory signal, such as that delivered by members of the B7 family to their receptor on the T-cell, CD28. Delivery of an antigen signal in the absence of costimulation does not result in productive immunity, but rather in anergy, a state of antigen-specific T-cell nonresponsiveness. To induce T-cell proliferation against B-cell malignancies, the tumor cell must first be induced to express B7 or the tumor antigen must be presented by an efficient antigen-presenting cell. Simple expression of B7 on the tumor cell alone, however, cannot reverse anergy. Reversal of anergy is a complex process involving stepwise repair of the T-cell defect and can be accomplished by prolonged exposure to interleukin-2, signaling through the CD2 pathway, followed by antigen presentation with B7-mediated costimulation. Successful immunotherapeutic strategies in the B-cell malignancies will likely require steps to reverse established anergy in the tumor-bearing host as well as effective tumor-antigen presentation.