A combination trial of vaccine plus ipilimumab in metastatic castration-resistant prostate cancer patients: immune correlates

• Published in: Cancer Immunology, Immunotherapy Vol. 63; no. 4; pp. 407 - 418
• Main Authors: Jochems, Caroline, Tucker, Jo A., Tsang, Kwong-Yok, Madan, Ravi A., Dahut, William L., Liewehr, David J., Steinberg, Seth M., Gulley, James L., Schlom, Jeffrey
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.04.2014; Springer Nature B.V
• Subjects: Adenocarcinoma - blood; Adenocarcinoma - drug therapy; Adenocarcinoma - secondary; Adenocarcinoma - therapy; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - therapeutic use; Antigens; Antigens, Differentiation - analysis; Cancer Research; Cancer therapies; Cancer Vaccines - administration & dosage; Cancer Vaccines - therapeutic use; Chemotherapy; Combined Modality Therapy; Cytotoxicity; FDA approval; Flow Cytometry; Hepatitis A Virus Cellular Receptor 2; Humans; Immunology; Immunophenotyping; Immunotherapy; Ipilimumab; Kaplan-Meier Estimate; Killer Cells, Natural - chemistry; Killer Cells, Natural - immunology; Lymphocyte Count; Lymphocytes; Male; Medical research; Medicine; Medicine & Public Health; Melanoma; Membrane Proteins - analysis; Metastasis; Oncology; Original Article; Prostate cancer; Prostate-Specific Antigen - blood; Prostatic Neoplasms, Castration-Resistant - blood; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - therapy; Radiation therapy; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Regulatory - chemistry; T-Lymphocytes, Regulatory - immunology; Th17 Cells - immunology; Vaccines; Vaccines, Synthetic - administration & dosage; Vaccines, Synthetic - therapeutic use; United States > US; NK cells; Vaccine; T cells; Ipilimumab; Immunotherapy; PROSTVAC
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-014-1524-0

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 CD4 EM ( 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.