Effective cooperation of monoclonal antibody and peptide vaccine for the treatment of mouse melanoma.

mAbs binding to tumor-associated surface Ags are therapeutically applied in a range of malignancies. Therapeutic vaccination only recently met with clinical success, and the first cancer vaccine received U.S. Food and Drug Administration approval last year. To improve current protocols, we combined peptide vaccines with mAb to the tyrosinase-related protein (TRP)-1 surface Ag for the treatment of B16F10 skin melanoma. Vaccine formulations with synthetic long peptides failed to elicit strong CD8 T cell responses to self-differentiation Ags gp100 and TRP-2, whereas altered peptide sequences recruited gp100-specific CD8 T cells from the endogenous repertoire with frequencies of 40%. However, these high frequencies were reached too late; large, progressively growing melanomas had already emerged. Addition of the TRP-1-directed mAb TA99 to the treatment protocol mediated eradication of s.c. lesions. The mode of action of the Ab did not depend on complement factor C3 and did not lead to improved Ag presentation and CD8 T cell immunity; rather, it recruited FcγR-bearing innate immune cells during early tumor control, thereby creating a window of time for the generation of protective cellular immunity. These data support the concept of combination therapy, in which passive transfer of mAbs is supplemented with cancer peptide vaccines. Moreover, we advocate that tumor Ag-specific T cell immunity directed against self-proteins can be exploited from the endogenous repertoire.