Existing data have strengthened the conviction that host immune responses may be augmented and used effectively against autologous tumors. The long- term goal is to develop a rationale for the use of cytokine vaccines that will enhance anti-tumor immune responses and induce the generation of anti- tumor effector mechanisms. We propose to achieve this goal by exploiting our knowledge of and experience in working with tumor-infiltrating lymphocytes (TIL). This proposal is based on data acquired from experiments using a combination therapy model, in which we have shown that when tumor-bearing mice receive an intraperitoneal injection of cyclophosphamide (CY) followed by the adoptive transfer of tumor-sensitized T cells, permanent tumor regression is induced in immune competent mice but not in immune-deficient strains. The underlying hypothesis is that resident TIL, those T cells associated with the progressing tumors, play a key role in the outcome of both conventional AIT as well as in the novel form of therapy involving gene transfer by making the tumor microenvironment more favorable for those T cells associated with the progressing tumors, play a key role in the outcome of both conventional AIT as well as in the novel form of therapy involving gene transfer by making the tumor microenvironment more favorable for those T cells that infiltrate the tumor mass after AIT or by responding directly to the gene products of transfected cells. We expect to attain our overall objectives by pursuing the following aims;
Aim 1. To show that a critical aspect of successful combination therapy is the ability of the resident population of TIL to undergo a secondary immune response after CY injection:
Aim 2 (complementary to Aim 1): To show that unsuccessful therapy of tumor- bearing immune-deficient mice is a consequence of the absence of reactive resident TIL and the failure to mount a secondary immune response. We will test three, possibly mutually-dependent hypotheses: (i) that immune- deficient mice are unable to induce permanent tumor regression after combination therapy because tumor cells regrow at a faster rate than effector mechanisms are generated; (ii) that tumor-associated class I-MHC or tumor-specific antigen is not (or only weakly) expressed resulting in the failure to generate effector mechanisms in a timely manner, and (iii) that the pattern of cytokine gene expression at the tumor site is different from that seen in immune competent mice after AIT and inhibits the generation of effector mechanisms:
Aim 3. To show that the successful use of IFN gamma gene-transfected TIL or transfected tumor cells as the vehicles for cytokine vaccination in the eradication of established tumors will depend initially on a basic response by resident TIL to the transfected gene product. The importance of this proposal is that the results will give us a better understanding of the mechanism of action of TIL in relation to host-mediated immune responses and provide a rational basis for the design of vaccines that will enhance the recognition of tumor cells and their ultimate destruction.
| Evans, R; Kamdar, S J; Duffy, T M et al. (1995) The therapeutic efficacy of murine anti-tumor T cells: freshly isolated T cells are more therapeutic than T cells expanded in vitro. Anticancer Res 15:441-7 |
| Evans, R; Kamdar, S J; Duffy, T M (1994) Qualitative and quantitative intratumoral changes in gene expression following cyclophosphamide injection and the adoptive transfer of T cells: the potential contribution of tumor-associated macrophages. Int J Cancer 56:568-73 |
