Issn Print: 0960-8931
Publication Date: 2006/09/01
Enhancement of vaccine-mediated antitumor immunity in melanoma patients by dacarbazine treatment
E. Proietti; I. Capone; P. Nisticò; P. Natali; B. Palermo; V. Ferraresi; F. Cognetti; M. Roselli; F. Belardelli; E. Proietti
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Author Information: Istituto Superiore di sanità
Excerpt
Chemotherapy is still the reference therapy for cancer patients in advanced stage. Although immunotherapy is a less conventional therapy, in the last few years it has been considered an attractive antitumor strategy. However, chemotherapy and immunotherapy have typically been considered as alternative therapies and, therefore, their relationship is poorly investigated. Our previous experience in animal model studies demonstrated that non-myeloablative treatment, as well as irradiation, can modulate the immune response and enhance the antitumor activity of adoptively transferred immune lymphocytes through the induction of a well-defined pattern of cytokines (‘cytokine storm’) occurring during the rebound phase after drug-induced myelodepletion. On this basis, we have designed a pilot clinical study for evaluating the effects of a chemotherapeutic treatment on immune responses to antitumor vaccination in melanoma patients. Ten HLA-A2 stage II/IV melanoma patients, with no evidence of disease, were enrolled and randomly assigned to one of two treatment groups: (i) vaccine (Melan-A/MART-1:26–35(27L) and gp100:209–217(210M) peptides formulated in Montanide ISA-51 plus 3 MU of IFN-α as an adjuvant); (ii) vaccine combined with dacarbazine (800 mg/mq). Primary and secondary end-points of the study were the assessment of antigen-specific CD8+ T cell responses and clinical responses, respectively. IFN-γ ELISPOT assay and tetramer analysis were used to monitor immune responses before and at different times during vaccination, in either ex-vivo or in-vitro expanded CD8+ T cells. A strong ex-vivo expansion of peptide-specific CD8+ T cells was observed only in patients treated with dacarbazine plus vaccine (four out of five patients). Moreover, in-vitro stimulation of CD8+ T cells demonstrated that patients receiving the combined treatment developed a peptide-specific immune response and ability of specifically lysing tumor cells consistently higher than the group treated with vaccine alone. Among the five patients treated with vaccine alone, four went into progression. In contrast, three out of five patients treated with vaccine plus darcabazine are at present disease free. These results suggest that the efficacy of cancer immunotherapy can be synergistically enhanced by combining cancer vaccines with conventional cancer treatment.
Sponsorship: The study was supported by the Italian Ministry of Health, project 3AO/F.
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