The goal of the proposed research is to obtain an experimental basis for the rational design of immunotherapeutic modalities capable of causing the regression of established immunogenic tumors. The results obtained will be applicable to immunotherapy against other replicating antigens. The proposed studies are based on the knowledge that progressive immunogenic tumors evoke the generation of a T cell-mediated concomitant immune response that is down-regulated by CD4+ suppressor T cells after the tumor grows beyond a certain critical size. It is intended to cause the regression of established tumors at a relatively late stage of their growth by preferentially depleting the host of suppressor T cells, and if necessary augmenting the immunity released from suppression by treating the host with IL-2, IL-1, or with bacterial superantigens (enterotoxins) that stimulate T cells via the variable region of the beta chain (Vbeta) of their T cell receptor (TCR). With a view to causing the regression of larger tumors, immunity released from suppression will be supplemented by adoptive immunization with T cells from immunized donors. The idea here is to show that adoptive immunotherapy can be more effective and made capable of causing regression of much larger tumors if steps are taken to preserve or augment the recipients own immune response. Preferential removal of suppressor T cells for the proposed studies will be achieved by treating tumor bearers with anti-Vbeta mAbs that destroy Vbeta T cell populations that contain suppressor T cells, but not effector/helper T cells. Preferential depletion of suppressor T cells will also be achieved later in tumor growth by taking advantage of the knowledge that suppressor T cells, but not effector/helper T cells, are actively replicating. Hence, suppressor T cells will be depleted by giving the tumor bearer antimitotic drugs. The released immunity will be analyzed in terms of the identity and physiology of the T cells that mediate it.
Showing the most recent 10 out of 27 publications
