ANTITUMOR-ACTIVITY OF CYTOTOXIC T-LYMPHOCYTES ELICITED WITH RECOMBINANT AND SYNTHETIC FORMS OF A MODEL TUMOR-ASSOCIATED ANTIGEN

The recent cloning of tumor-associated antigens (TAAs) recognized by C D8(+) T lymphocytes (T-CD8+) has made it possible to use recombinant a nd synthetic forms of TAAs to generate T-CD8+ with anti-tumor activity . To explore new therapeutic strategies in a mouse model, we retrovira lly transduced the experimental murine tumor CT26 (H-2(d)), with the l acZ gene encoding our model TAA, beta-galactosidase (beta-gal). The tr ansduced cell line, CT26.CL25, grew as rapidly and as lethally as the parental cell line in normal, immunocompetent animals. In an attempt t o elicit T-CD8+ directed against our model TAA by using purely recombi nant and synthetic forms of our model TAA, we synthesized a nine-amino -acid long immunodominant peptide of beta-gal (TPH-PARIGL), correspond ing to amino acid residues 876-884, which was known to be presented by the L(d) major histocompatibility complex (MHC) class I molecule, and a recombinant vaccinia virus encoding the full-length beta-gal protei n (VJS6). Splenocytes obtained from naive mice and co-cultured with be ta-gal peptide could not be expanded in primary ex vivo cultures. Howe ver, mice immunized with VJS6, but not with a control recombinant vacc inia virus, yielded splenocytes that were capable of specifically lysi ng CT26.CL25 in vitro after co-culture with beta-gal peptide. Most sig nificantly, adoptive transfer of these cells could effectively treat m ice bearing 3-day-old established pulmonary metastases. These observat ions show that therapeutic T-CD8+ directed against a model TAA could b e generated by using purely recombinant and synthetic forms of this an tigen. These findings point the way to a potentially useful immunother apeutic strategy, which has been made possible by the recent cloning o f immunogenic TAAs that are expressed by human malignancies.