title: A combination trial of vaccine plus ipilimumab in metastatic castration-resistant prostate cancer patients: immune correlates.
abstract: We recently reported the clinical results of a Phase I trial combining ipilimumab with a vaccine containing transgenes for prostate-specific antigen (PSA) and for a triad of costimulatory molecules (PROSTVAC) in patients with metastatic castration-resistant prostate cancer. Thirty patients were treated with escalating ipilimumab and a fixed dose of vaccine. Of 24 chemotherapy-naïve patients, 58 % had a PSA decline. Combination therapy did not exacerbate the immune-related adverse events associated with ipilimumab. Here, we present updated survival data and an evaluation of 36 immune cell subsets pre- and post-therapy. Peripheral blood mononuclear cells were collected before therapy, at 13 days and at 70 days post-initiation of therapy, and phenotyped by flow cytometry for the subsets of T cells, regulatory T cells, natural killer cells, and myeloid-derived suppressor cells. Associations between overall survival (OS) and immune cell subsets prior to treatment, and the change in a given immune cell subset 70 days post-initiation of therapy, were evaluated. The median OS was 2.63 years (1.77-3.45). There were trends toward associations for longer OS and certain immune cell subsets before immunotherapy: lower PD-1(+)Tim-3(NEG)CD4EM (P = 0.005, adjusted P = 0.010), higher PD-1(NEG)Tim-3(+)CD8 (P = 0.002, adjusted P = 0.004), and a higher number of CTLA-4(NEG) Tregs (P = 0.005, adjusted P = 0.010). We also found that an increase in Tim-3(+) natural killer cells post- versus pre-vaccination associated with longer OS (P = 0.0074, adjusted P = 0.015). These results should be considered as hypothesis generating and should be further evaluated in larger immunotherapy trials.
authors: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD, 20892, USA.
authors: Caroline
authors: C
authors: Jochems
authors: Jo A
authors: JA
authors: Tucker
authors: Kwong-Yok
authors: KY
authors: Tsang
authors: Ravi A
authors: RA
authors: Madan
authors: William L
authors: WL
authors: Dahut
authors: David J
authors: DJ
authors: Liewehr
authors: Seth M
authors: SM
authors: Steinberg
authors: James L
authors: JL
authors: Gulley
authors: Jeffrey
authors: J
authors: Schlom
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy / Q000556:secondary* / Q000628:therapy; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D000943:Antigens, Differentiation / Q000032:analysis; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D005434:Flow Cytometry; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D016130:Immunophenotyping; D000074324:Ipilimumab; D053208:Kaplan-Meier Estimate; D007694:Killer Cells, Natural / Q000737:chemistry / Q000276:immunology; D018655:Lymphocyte Count; D008297:Male; D008565:Membrane Proteins / Q000032:analysis; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy / Q000628:therapy*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D019496:Cancer Vaccines; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D000074324:Ipilimumab; D008565:Membrane Proteins; C588274:PROSTVAC; D014614:Vaccines, Synthetic; D017430:Prostate-Specific Antigen