title: Preexisting Levels of CD4 T Cells Expressing PD-1 Are Related to Overall Survival in Prostate Cancer Patients Treated with Ipilimumab.
abstract: Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockade can induce tumor regression and improved survival in cancer patients. This treatment can enhance adaptive immune responses without an exogenous vaccine, but the immunologic biomarkers associated with improved clinical outcome in cancer patients are not fully established. A phase Ib trial in patients with metastatic, castration-resistant prostate cancer was performed combining ipilimumab with sargramostim (GM-CSF). In addition to evaluating ipilimumab dose, patients were followed clinically for response and overall survival, and for immunomodulation of circulating T cells. PSA declines of ≥50% and radiographic responses were observed at doses of ≥3 mg/kg/dose. Timing of clinical responses could be either immediate or delayed. Durable responses were also observed off treatment. A subset of patients experienced long-term survival with or without objective clinical responses. The relationship between T-cell phenotype in peripheral blood and overall survival was examined retrospectively. We found that the treatment induced an increase in the levels of CD4(+) effector T (Teff) cells, regulatory T cells, PD-1(+) CD4 Teff cells, and PD-1(+) CD8 T cells. However, these increased levels were not associated with overall survival. Instead, low pretreatment baseline levels of PD-1(+) CD4 Teff cells were found to correlate with longer overall survival. Furthermore, baseline levels of PD-1(+) CD4 Teff cells from patients with shorter overall survival were higher than from cancer-free male control subjects. These results suggest that preexisting expression of immunologic checkpoint marker PD-1 on CD4 Teff cells may help identify patients that may benefit from ipilimumab treatment.
authors.affiliation: Division of Hematology/Oncology, University of California, San Francisco, California.
authors.forename: Serena S
authors.initials: SS
authors.lastname: Kwek
authors.affiliation: Division of Hematology/Oncology, University of California, San Francisco, California.
authors.forename: Jera
authors.initials: J
authors.lastname: Lewis
authors.affiliation: Division of Hematology/Oncology, University of California, San Francisco, California. UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Vivian
authors.initials: V
authors.lastname: Weinberg
authors.affiliation: Division of Hematology/Oncology, University of California, San Francisco, California.
authors.forename: Samantha K
authors.initials: SK
authors.lastname: Greaney
authors.affiliation: Division of Hematology/Oncology, University of California, San Francisco, California.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Harzstark
authors.affiliation: Division of Hematology/Oncology, University of California, San Francisco, California.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Lin
authors.affiliation: Division of Hematology/Oncology, University of California, San Francisco, California. UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Ryan
authors.affiliation: Division of Hematology/Oncology, University of California, San Francisco, California. UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Small
authors.affiliation: Division of Hematology/Oncology, University of California, San Francisco, California. UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California. lfong@medicine.ucsf.edu.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Fong
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D005500:Follow-Up Studies; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D000074324:Ipilimumab; D007610:Kallikreins / Q000097:blood; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000097:blood; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000097:blood*; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D016176:T-Lymphocyte Subsets / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D060908:CTLA-4 Antigen; D000074324:Ipilimumab; D009363:Neoplasm Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011994:Recombinant Proteins; C081222:sargramostim; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen