title: Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF.
abstract: 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.
authors.affiliation: Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California 94143, USA. lawrence.fong@ucsf.edu
authors.forename: Lawrence
authors.initials: L
authors.lastname: Fong
authors.forename: Serena S
authors.initials: SS
authors.lastname: Kwek
authors.forename: Shaun
authors.initials: S
authors.lastname: O'Brien
authors.forename: Brian
authors.initials: B
authors.lastname: Kavanagh
authors.forename: Douglas G
authors.initials: DG
authors.lastname: McNeel
authors.forename: Vivian
authors.initials: V
authors.lastname: Weinberg
authors.forename: Amy M
authors.initials: AM
authors.lastname: Lin
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rosenberg
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Ryan
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Small
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D015703:Antigens, CD / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods*; D000074324:Ipilimumab; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000276:immunology / Q000628:therapy*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000074324:Ipilimumab; D016178:Granulocyte-Macrophage Colony-Stimulating Factor