Potentiating Endogenous Antitumor Immunity to Prostate Cancer through Combination Immunotherapy with CTLA4 Blockade and GM-CSF
Lawrence Fong1,2, Serena S. Kwek1,2, Shaun O'Brien1,2, Brian Kavanagh1,2, Douglas G. McNeel4, Vivian Weinberg3, Amy M. Lin1, Jonathan Rosenberg1, Charles J. Ryan1, Brian I. Rini5 and Eric J. Small1
1 Division of Hematology/Oncology, 2 Immunology Program, and 3 UCSF H. Diller Comprehensive Cancer Center, Biostatistics Core, University of California, San Francisco, San Francisco, California; 4 Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, Wisconsin; and 5 Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
Requests for reprints: Lawrence Fong, University of California, San Francisco, 513 Parnassus Avenue, Box 0511, San Francisco, CA 94143. Phone: 415-514-3160; Fax: 415-476-0459; E-mail: lawrence.fong{at}ucsf.edu.
CTL-associated antigen 4 (CTLA4) is a costimulatory molecule expressed on activated T cells that delivers an inhibitory signal to these T cells. CTLA4 blockade with antibody treatment has been shown to augment antitumor immunity in animal models and is being developed as a treatment for cancer patients. As has been seen in preclinical models, combining CTLA4 blockade and granulocyte macrophage colony-stimulating factor (GM-CSF)–based immunotherapies can enhance the antitumor efficacy of this approach. We therefore examined whether CTLA4 blockade could be combined with GM-CSF administration. We treated 24 patients with metastatic, castration-resistant prostate cancer in a phase I trial where sequential cohorts were treated with increasing doses of ipilimumab, a fully human anti-CTLA4 antibody. Study subjects also received s.c. injections of GM-CSF at a fixed dose. Of the six patients treated at the highest dose level, three had confirmed PSA declines of >50%, including one patient that had a partial response in visceral metastases. Expansion of activated, circulating CD25+ CD69+ CD8+ T cells occurred more frequently at higher doses of treatment and was greater in magnitude than was seen in patients who received the same doses of either ipilimumab or GM-CSF alone. By screening sera with protein arrays, we showed that our treatment can induce antibody responses to NY-ESO-1. These results show that this combination immunotherapy can induce the expansion not only of activated effector CD8 T cells in vivo but also of T cells that are specific for known tumor-associated antigens from the endogenous immune repertoire. [Cancer Res 2009;69(2):609–15] |
