title: T cell profiling reveals high CD4+CTLA-4 + T cell frequency as dominant predictor for survival after prostate GVAX/ipilimumab treatment.
abstract: Immune checkpoint blockade enhances antitumor responses, but can also lead to severe immune-related adverse events (IRAE). To avoid unnecessary exposure to these potentially hazardous agents, it is important to identify biomarkers that correlate with clinical activity and can be used to select patients that will benefit from immune checkpoint blockade. To understand the consequences of CTLA-4 blockade and identify biomarkers for clinical efficacy and/or survival, an exploratory T cell monitoring study was performed in a phase I/II dose escalation/expansion trial (n = 28) of combined Prostate GVAX/ipilimumab immunotherapy. Phenotypic T cell monitoring in peripheral blood before and after Prostate GVAX/ipilimumab treatment revealed striking differences between patients who benefited from therapy and patients that did not. Treatment-induced rises in absolute lymphocyte counts, CD4(+) T cell differentiation, and CD4(+) and CD8(+) T cell activation were all associated with clinical benefit. Moreover, significantly prolonged overall survival (OS) was observed for patients with high pre-treatment frequencies of CD4(+)CTLA-4(+), CD4(+)PD-1(+), or differentiated (i.e., non-naive) CD8(+) T cells or low pre-treatment frequencies of differentiated CD4(+) or regulatory T cells. Unsupervised clustering of these immune biomarkers revealed cancer-related expression of CTLA-4(+) in CD4(+) T cells to be a dominant predictor for survival after Prostate GVAX/ipilimumab therapy and to thus provide a putative and much-needed biomarker for patient selection prior to therapeutic CTLA4 blockade.
authors.affiliation: Department of Medical Oncology, Cancer Center Amsterdam, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. s.santegoets@vumc.nl
authors.forename: Saskia J A M
authors.initials: SJ
authors.lastname: Santegoets
authors.forename: Anita G M
authors.initials: AG
authors.lastname: Stam
authors.forename: Sinéad M
authors.initials: SM
authors.lastname: Lougheed
authors.forename: Helen
authors.initials: H
authors.lastname: Gall
authors.forename: Petra E T
authors.initials: PE
authors.lastname: Scholten
authors.forename: Martine
authors.initials: M
authors.lastname: Reijm
authors.forename: Karin
authors.initials: K
authors.lastname: Jooss
authors.forename: Natalie
authors.initials: N
authors.lastname: Sacks
authors.forename: Kristen
authors.initials: K
authors.lastname: Hege
authors.forename: Israel
authors.initials: I
authors.lastname: Lowy
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Cuillerot
authors.forename: B Mary E
authors.initials: BM
authors.lastname: von Blomberg
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: Alfons J M
authors.initials: AJ
authors.lastname: van den Eertwegh
authors.forename: Winald R
authors.initials: WR
authors.lastname: Gerritsen
authors.forename: Tanja D
authors.initials: TD
authors.lastname: de Gruijl
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D060908:CTLA-4 Antigen / Q000032:analysis / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D000074324:Ipilimumab; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D011471:Prostatic Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; D000074324:Ipilimumab; D016178:Granulocyte-Macrophage Colony-Stimulating Factor