ANTIGEN-SPECIFIC REGRESSION OF ESTABLISHED TUMORS INDUCED BY ACTIVE IMMUNIZATION WITH IRRADIATED IL-12-TRANSFECTED BUT NOT B7-1-TRANSFECTEDTUMOR-CELLS

Transfection of modestly immunogenic tumors to express B7 family co-st imulator molecules results in their rejection by syngeneic mice, sugge sting a possible clinical application in cancer patients, Immunization of naive mice with irradiated B7-1-transfected P1.HTR cells is suffic ient to induce specific cytolytic T lymphocytes (CTL) and to protect a gainst tumor challenge, However, patients to be treated will have an e xisting tumor burden; thus, preclinical models should examine therapeu tic efficacy in an established tumor setting, Contrary to expectations , immunization of mice with irradiated B7-1-transfected P1.HTR cells h ad no impact on the growth of pre-established control-transfected tumo rs, Mice bearing control-transfected P1.HTR tumors successfully reject ed living B7-1 transfectants on the contralateral flank, demonstrating the ability of tumor-bearing mice to respond to B7 co-stimulation. In asmuch as IL-12 is another important factor for CTL maturation, P1.HTR transfectants expressing B7-1 and/or IL-12 were then constructed, Rem arkably, regression of preestablished tumors was achieved following im munization with irradiated IL-12 transfectants, even without co-expres sion of B7-1, Rejection required a shared antigen with the tumor used for immunization, could not be reproduced with rIL-12 alone, depended on host T lymphocytes and correlated with a high IFN-gamma-producing T cell phenotype. In addition, IL-12-facilitated tumor rejection requir ed co-operation with a CTLA-4 ligand provided by the host, and correla ted with up-regulation of B7-1 and B7-2 on host antigen-presenting cel ls, Thus, active immunization in the established tumor setting is bene fitted greatly by the provision of IL-12, which may recruit participat ion of sufficient B7 co-stimulation from the host that it need not be provided exogenously.