Immune responses causing tumor destruction can be induced by presentation of tumor selective epitopes by the MHC of cancer cells or after antigen uptake, processing and presentation by professional APC. While tumor regression has been seen in preclinical models and some promising clinical results have been obtained, much remains to be done to make such responses effective against established rumors. This proposal is based on two discoveries by the applicant's (former) group, showing that increased costimulation via CD28 and increased signalling via the 4-1BB receptor on activated T lymphocytes, facilitates the induction of a tumoricidal response against various mouse tumors. The response so induced can cause the destruction of established tumors of very low immunogenicity that have resisted other forms of therapy, and it is accompanied by high, antigen-specific and MHC restricted CTL activity. The goal of the proposed work is to translate this information towards the construction of tumor vaccines for therapeutic use in man. As our first aim, cells will be cultivated from several different human carcinomas (ovary, colon, breast, lung or kidney), expressing MHC class I molecules of the A2 haplotype, and combined with autologous lymphocytes from tumors or blood to activate/generate tumor-selective CTL and T helper responses of the Th1 type. This will be done in the presence or absence of costimulation via B7-CD28 and/or of """"""""triggering"""""""" activated T cells via 4-1BB, provided either by a monoclonal antibody to CD28 or 4-1BB or by transfecting the respective ligands (CD80 and/or CD86, 4-1BB ligand) into the tumor cells. Experiments will also be performed to study whether a similar approach affects the proliferation, lymphokine production, and antigen-selective CTL activity of established, tumor-reactive T cell clones/lines.
Our second aim i s to investigate whether costimulation and/or 4-1BB """"""""triggering"""""""" facilitates the activation/generation of tumor-reactive T cells in the presence of a known inhibitor of CTL and Th1 activity, TGF-beta, or a Th2 type lymphokine such as IL4, or putative inhibitory """"""""factors"""""""" present in autologous malignant effusions. This will be studied both with lymphocytes harvested directly from tumors or blood and with tumor-reactive T cell clones. The information obtained should guide the construction of tumor cell-based vaccines for therapeutic use in man, and should have an impact also on other approaches to tumor vaccination by illustrating the role, in tumor immunity, of signalling via CD28 and 4-1BB.
