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5-AZA-2'-Deoxycytidine in Cancer Immunotherapy: A Mouse to Man Story

Cancer Bioimmunotherapy Unit, Department of Medical Oncology, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy

Pier Giorgio Natali

Laboratory of Immunology, Centro di Ricerca Sperimentale, Istituto Regina Elena, Rome, Italy

Michele Maio

Cancer Bioimmunotherapy Unit, Department of Medical Oncology, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy and Division of Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy

To the Editor:

We read with great interest the article by Guo et al. (1) reporting that the DNA hypomethylating agent 5-aza-2'-deoxycytidine (5-AZA-CdR) induced a persistent expression of the murine cancer/testis antigen (CTA) P1A in different cultured murine tumors. Systemic administration of 5-AZA-CdR to BALB/c mice grafted with 4T1 mammary adenocarcinoma was also reported to induce a de novo expression of P1A on neoplastic cells that significantly reduced their metastatic potential to the lung; this therapeutic effect of 5-AZA-CdR on lung metastasization was synergized by the adoptive transfer of P1A-specific CTL. Based on their findings in the murine system, the authors agreeably concluded that 5-AZA-CdR represents a useful drug to design novel strategies of combined chemoimmunotherapy of cancer.

We have recently drawn similar conclusions in humans, based on in vitro data we (2, 3) and others (4–6) had previously generated, and on our in vivo evidences obtained in different solid and hemopoietic malignancies (7, 8). Among the major findings, 5-AZA-CdR was shown to (a) persistently induce and up-regulate the concomitant expression of multiple members of different CTA families in cultured neoplastic cells, which became efficiently recognized by anti-CTA CTL (2); to (b) revert the constitutive intratumor heterogeneity of CTA expression, allowing a homogeneous recognition of transformed cells by anti-CTA CTL (3); to (c) induce and up-regulate the expression of several CTA in human melanomas grafted into BALB/c nu/nu mice (7); and to (d) induce the expression of different CTA in circulating neoplastic cells of patients affected by acute myeloid leukemias or myelodysplastic syndromes after a single i.v. administration of the drug (8).

In addition to these evidences, using human melanoma as a "model disease," we have now gained additional information on the immunomodulatory properties of 5-AZA-CdR in vivo, which additionally help to define its prospective clinical potential in patients with cancer. Quantitative real-time reverse transcriptase-PCR analysis showed a strong de novo expression of NY-ESO-1 (9 x 10^–4 NY-ESO-1 molecules/ß-actin molecules) in Mel 313 melanoma xenografts excised from BALB/c nu/nu mice 4 days after the last administration of 5-AZA-CdR. Although it progressively decreased with time, NY-ESO-1 expression was still detectable (8 x 10^–5 NY-ESO-1 molecules/ß-actin molecules) in xenografts excised 30 days following the last treatment. This persistent expression of NY-ESO-1 in vivo was further confirmed at the protein level by the staining of melanoma xenografts with the anti–NY-ESO-1 monoclonal antibody B9.8 (kindly provided by Dr. Giulio C. Spagnoli, Department of Surgery, Division of Research, University of Basel, Basel, Switzerland). Consistent with these data, treatment with 5-AZA-CdR also induced a long-lasting up-regulation of the constitutive expression of MAGE-3 in Mel 313 melanoma xenografts, both at the molecular and protein level (data not shown).

The ability of 5-AZA-CdR to persistently induce and up-regulate in vivo the expression of NY-ESO-1 and MAGE-3, which are the most utilized therapeutic CTA at present (2), provides further strong support to its immunotherapeutic potential in the clinical setting. In fact, the long-lasting modulation of the expression of therapeutic CTA on neoplastic cells, along with the complex of available data on the immunomodulatory activity of 5-AZA-CdR in human tumors and with the recent evidences provided by Guo et al. in the murine system (1), provides a strong scientific rationale to implement novel immunotherapeutic approaches combining active and/or adoptive CTA-based immunotherapy with systemic administration of 5-AZA-CdR in the clinical setting.

Acknowledgments

Grant support: This work was supported in part by a grant from the Associazione Italiana per la Ricerca sul Cancro (M. Maio).

References

1. Guo ZS, Hong JA, Irvine KR, et al. De novo induction of a cancer/testis antigen by 5-aza-2'-deoxycytidine augments adoptive immunotherapy in a murine tumor model. Cancer Res 2006;66:1105–13.[Abstract/Free Full Text]
2. Maio M, Coral S, Fratta E, Altomonte M, Sigalotti L. Epigenetic targets for immune intervention in human malignancies. Oncogene 2003;22:6484–8.[CrossRef][Medline]
3. Sigalotti L, Fratta E, Coral S, et al. Intratumor heterogeneity of cancer/testis antigens expression in human cutaneous melanoma is methylation-regulated and functionally reverted by 5-aza-2'-deoxycytidine. Cancer Res 2004;64:9167–71.[Abstract/Free Full Text]
4. Weber J, Salgaller M, Samid D, et al. Expression of the MAGE-1 tumor antigen is up-regulated by the demethylating agent 5-aza-2'-deoxycytidine. Cancer Res 1994;54:1766–71.[Abstract/Free Full Text]
5. Lethe B, Lucas S, Michaux L, et al. LAGE-1, a new gene with tumor specificity. Int J Cancer 1998;76:903–8.[CrossRef][Medline]
6. Lee L, Wang RF, Wang X, et al. NY-ESO-1 may be a potential target for lung cancer immunotherapy. Cancer J Sci Am 1999;5:20–5.[Medline]
7. Coral S, Sigalotti L, Colizzi F, et al. Phenotypic and functional changes of human melanoma xenografts induced by DNA hypomethylation: immunotherapeutic implications. J Cell Physiol 2006;207:58–66.[CrossRef][Medline]
8. Sigalotti L, Altomonte M, Colizzi F, et al. 5-Aza-2'-deoxycytidine (decitabine) treatment of hematopoietic malignancies: a multimechanism therapeutic approach? Blood 2003;101:4644–6.[Free Full Text]

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