Adjuvant vaccination with melanoma antigen pulsed dendritic cells (DCs) in stage III melanoma patients.

Author(s): S. Markowicz, Z. I. Nowecki, P. Rutkowski, A. W. Lipkowski, A. Jakubowska-Mucka, T. Switaj, M. Biernacka, A. Misicka, J. A. Walewski, W. Ruka; M. Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland; M. Sklodowska-Curie Memorial Cancer Center , Warsaw, Poland; Medical Research Center Polish Academy of Sciences, Warsaw, Poland

Abstract:

Background: This is a pilot study evaluating of high-risk melanoma patients (pts) treated with peptide-DC vaccine after lymphadenectomy (LND). DC vaccination was designed to induce the immune response against melanoma antigens in melanoma pts who remain at high risk of dissemination after LND.

Methods: DCs were generated from the bone marrow with the use GM-CSF, SCF, FLT3-L and TNFa or from peripheral blood adherent monocytes with GM-CSF and IL-4. DCs pulsed with HLA-A2-binding TYR, MART-1 and gp100 peptides and/or HLA-A1-binding MAGE-1, MAGE-3 peptides, tumor lysate if available, or with tracer antigen keyhole limpet hemocyanin (KLH), were injected sc 9 times within 8 months (mos). Boost injections were performed after 12 and 24 mos. Vaccinated pts were matched to unvaccinated controls (22 of 587) by sex, number of metastatic lymph nodes, extracapsular involvement, completion or therapeutic LND, Breslow stage (T), and ulceration.

Results: HLA-A2⁺, -A1⁺ or -A3⁺ melanoma pts (n=22), stage III, N1b-N3, enrolled between Sept. 2002 and Apr. 2004, received 5-16 vaccinations (median: 11) within 2 yrs. Cutaneous delayed type hypersensitivity (DTH) to melanoma peptides was induced in 12 of 22 pts. Peptide-specific IFNg producing CD8⁺ cells were detected in peripheral blood of 13 of 19 pts after vaccination. At least one of these responses to melanoma antigens was elicited in 17 of 22 pts. DTH to KLH was positive in 15 of 22 pts. Nine vaccinated pts are free of disease, and 1 is stable by Dec. 2008 (follow up is 58-76 mos after LND). Survival analysis for vaccinated pts and matched controls is presented in the Table.

Conclusions: The DC/peptide vaccine elicited immune responses to melanoma antigens. Vaccinated pts had clinically substantially longer overall survival (OS) and disease free survival (DFS) than matched control. OS was associated with the immune responsiveness to melanoma antigens and to KLH.