By Will Boggs, MD
NEW YORK (Reuters Health) – Pretreatment with dacarbazine, a DNA alkylating agent, enhances vaccine-induced antitumor immunity in patients with melanoma, according to a report in the January 1st International Journal of Cancer.
“It is possible to combine certain chemotherapeutic agents with immunotherapy and, paradoxically, certain chemotherapeutic agents can potentiate the vaccine-induced immune response, thus rendering anticancer vaccination effective in preventing disease recurrence,” Dr. Enrico Proietti from Istituto Superiore di Sanita in Rome told Reuters Health.
Dr. Proietti and colleagues explored whether the administration of dacarbazine in disease-free melanoma patients 24 hours before each of 10 peptide vaccine doses could result in an improved cellular immune response to vaccine and in an early upregulation of immune response-related genes.
The strength of the CD8+ T-cell antitumor response was significantly higher “along all the course of vaccination” when patients were pretreated with dacarbazine than when patients received vaccine without pretreatment, the authors report.
The percentage of effector memory T cells from dacarbazine-treated patients was consistently higher than from patients treated with vaccine alone, the researchers note, and dacarbazine treatment induced a long-lasting persistence of peptide-specific CD8+ T cells recognizing tumor antigen.
Dacarbazine treatment was associated with upregulation of 138 genes and downregulation of 176 genes, the researchers said. Genes most upregulated included those involved in cytokine production and leukocyte activation, immune response, and cell motility, whereas downregulated genes reflected the mild hematological toxicity induced by the chemotherapy.
“The therapeutic strategy we suggest is based on the hypothesis that a transient, weak insult on the lympho-hemopoietic system, carried out by chemotherapy administration, activates homeostatic mechanisms which, in a narrow window of time, can be positively exploited to potentiate immune responses that, otherwise, will fail to become effective,” Dr. Proietti explained. “This principle needs further, extensive studies to be understood in depth, and its application could be extend beyond the cancer vaccines to chronic infectious disease treatment, including AIDS and tuberculosis.”
“We are analyzing thousands of CD8+ T cell clones obtained from the patients before and after the two kinds of treatments, vaccination alone or dacarbazine plus vaccination,” coauthor Dr. Paola Nistico from Regina Elena Cancer Institute, Rome told Reuters Health. “The analysis of the sequences of the clones (and) the functional characterization of these anti-Melan-A CD8 T cells suggest that dacarbazine significantly affects the anti-Melan-A specific T cell repertoire.”
Int J Cancer 2009;124:130-139.