In Response:
We agree with Coral and colleagues that preclinical studies have thus far provided a sound and strong scientific rationale to implement novel therapeutic approaches combining active and/or passive immunotherapy with systemic administration of 5-aza-2′-deoxycytidine (5-AZA-CdR, or decitabine) for human solid tumors as well as leukemia. The data have been accumulated from a number of studies on the induction of various human cancer/testis antigens (CTA) in vitro. Most recently, the induction of murine CTA P1A in various syngeneic tumors in mouse models ( 1) and human CTAs in human tumor xenografts in nude mice ( 2) has been shown following systemic administration of 5-AZA-CdR. Moving one step forward, we showed that the de novo–induced P1A in tumor cells can be used as a target for adoptive immunotherapy of cancer in a mouse model ( 1).
After successful clinical trials, 5-AZA-CdR has been approved by the U.S. Food and Drug Administration for the treatment of patients with myelodysplastic syndromes. As for solid tumors, several clinical trials (phase I) using 5-AZA-CdR for the induction of CTAs and other genes and its toxicity in patients have been conducted recently ( 3– 5). Samlowski and coworkers have shown that a 7-day continuous i.v. infusion of decitabine could lead to DNA hypomethylation and activation of the MAGE-1 gene promoter in the peripheral blood mononuclear cells of patients with solid tumors ( 3). In conjunction with high-dose interleukin 2, the main toxicity of decitabine is neutropenia in most patients with melanoma or renal cell carcinoma ( 4). Our group at the National Cancer Institute has evaluated the induction of NY-ESO-1, MAGE-3, and p16 genes using decitabine in patients with cancers of the lung, esophagus, or pleura. The results showed that gene induction was observed in up to 36% of patients with cancer ( 5). Obviously, additional clinical trials need to be conducted, with optimized dose/schedules of decitabine alone or in conjunction with other types of agents such as histone deacetylase inhibitor, before we know definitely that this regimen of gene induction will work well in patients with solid cancers.
Our hypothesis has been that treatment with epigenetic remodeling agents may enhance the immunogenicity of cancer through the up-regulation of immune-related genes. The genes may include those for CTAs, MHC class I and II antigens that were silenced by epigenetic mechanisms, as well as cytokines and costimulatory molecules for T cells, dendritic cells, and natural killer cells. 1 The treatment sensitizes the cancer to the subsequent immunotherapy targeting CTAs that were induced or up-regulated by decitabine, or other types of tumor-associated antigens. We envision that this combination treatment, immunotherapy following epigenetic remodeling, may become a new avenue for cancer therapy.
- ©2007 American Association for Cancer Research.
Volume 67, Issue 6
