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Blood, 19 February 2009, Vol. 113, No. 8, pp. 1651-1660.
Prepublished online as a Blood First Edition Paper on December 12, 2008; DOI 10.1182/blood-2008-07-168666.
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Submitted July 17, 2008
Accepted November 19, 2008
Peripheral blood lymphocytes genetically modified to express the self/tumor antigen MAGE-A3 induce antitumor immune responses in cancer patients
Raffaella Fontana, Marco Bregni, Arcadi Cipponi, Laura Raccosta, Cristina Rainelli, Daniela Maggioni, Francesca Lunghi, Fabio Ciceri, Sylvain Mukenge, Claudio Doglioni, Didier Colau, Pierre G. Coulie, Claudio Bordignon*, Catia Traversari, and Vincenzo Russo
Cancer Gene Therapy Unit, Cancer Immunotherapy and Gene Therapy Program, Department of Oncology, Scientific Institute S. Raffaele, Milan, Italy
Strategic Program of Oncology, Scientific Institute S.Raffaele, Milan, Italy
Bone Marrow Transplantation Unit, Scientific Institute S.Raffaele, Milan, Italy
Department of Surgery, Scientific Institute S.Raffaele, Milan, Italy
Department of Pathology, Scientific Institute S.Raffaele, Milan, Italy
Ludwig Institute for Cancer Research, Brussels, Belgium
de Duve Institute, Universite Catholique de Louvain, Brussels, Belgium
Universita Vita-Salute S.Raffaele, Milan, Italy
MolMed S.p.A., Milan, Italy
* Corresponding author; email: claudio.bordignon{at}hsr.it.
DC targeting in vivo has recently been shown to confer strong and protective CTL-based immunity in tumor murine models. Our group has recently demonstrated in preclinical models that the infusion of genetically modified lymphocytes (GML) expressing the self/tumor antigen TRP-2 is able to elicit functional TRP-2-specific effectors with antitumor activity by targeting DC in vivo. Here we have analyzed vaccine- and tumor-specific immune responses of ten melanoma patients treated with autologous GML expressing the cancer-germline gene MAGE-A3. Three out of ten patients treated with MAGE-A3-GML showed a strong increase of circulating anti-MAGE-A3 T cells, and developed skin Delayed-Type Hypersensitivity to MAGE-A3. Interestingly, in two of these patients, with progressive and measurable tumors at study entry, anti-MAGE-A3 T cells were detected not only in the blood but also within tumors resected after vaccination. These results demonstrate that the infusion of MAGE-A3-GML elicits antitumor T cells, which are capable of trafficking to inflamed tissues and of infiltrating tumors. Clinical studies on larger group of patients are needed to evaluate the clinical efficacy of such a strategy.
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