Chemotherapy enhances vaccine-induced antitumor immunity in melanoma patients.
Combination of chemotherapy with cancer vaccines is currently regarded as a potentially valuable therapeutic approach for the treatment of some metastatic tumors, but optimal modalities remain unknown. We designed a phase I/II pilot study for evaluating the effects of dacarbazine (DTIC) on the immune response in HLA-A2(+) disease-free melanoma patients who received anticancer vaccination 1 day following chemotherapy (800 mg/mq i.v.). The vaccine, consisting of a combination of HLA-A2 restricted melanoma antigen A (Melan-A/MART-1) and gp100 analog peptides (250 microg each, i.d.), was administered in combination or not with DTIC to 2 patient groups. The combined treatment is nontoxic. The comparative immune monitoring demonstrates that patients receiving DTIC 1 day before the vaccination have a significantly improved long-lasting memory CD8(+) T cell response. Of relevance, these CD8(+) T cells recognize and lyse HLA-A2(+)/Melan-A(+) tumor cell lines. Global transcriptional analysis of peripheral blood mononuclear cells (PBMC) revealed a DTIC-induced activation of genes involved in cytokine production, leukocyte activation, immune response and cell motility that can favorably condition tumor antigen-specific CD8(+) T cell responses. This study represents a proof in humans of a chemotherapy-induced enhancement of CD8(+) memory T cell response to cancer vaccines, which opens new opportunities to design novel effective combined therapies improving cancer vaccination effectiveness.
Department of Experimental Oncology, Regina Elena Cancer Institute, Rome, Italy. nistico@ifo.it
Paola
P
Nisticò
Imerio
I
Capone
Belinda
B
Palermo
Duilia
D
Del Bello
Virginia
V
Ferraresi
Federica
F
Moschella
Eleonora
E
Aricò
Mara
M
Valentini
Laura
L
Bracci
Francesco
F
Cognetti
Mariangela
M
Ciccarese
Giuseppe
G
Vercillo
Mario
M
Roselli
Emanuela
E
Fossile
Maria Elena
ME
Tosti
Ena
E
Wang
Francesco
F
Marincola
Luisa
L
Imberti
Caterina
C
Catricalà
Pier Giorgio
PG
Natali
Filippo
F
Belardelli
Enrico
E
Proietti
D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D019496:Cancer Vaccines / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D016898:Interferon-alpha / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010865:Pilot Projects; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D016898:Interferon-alpha