title: Activated lymphocyte recruitment into the tumor microenvironment following preoperative sipuleucel-T for localized prostate cancer.
abstract: BACKGROUND
  Sipuleucel-T is a US Food and Drug Administration-approved immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Its mechanism of action is not fully understood. This prospective trial evaluated the direct immune effects of systemically administered sipuleucel-T on prostatic cancer tissue in the preoperative setting.
  
  
  METHODS
  Patients with untreated localized prostate cancer were treated on an open-label Phase II study of sipuleucel-T prior to planned radical prostatectomy (RP). Immune infiltrates in RP specimens (posttreatment) and in paired pretreatment biopsies were evaluated by immunohistochemistry (IHC). Correlations between circulating immune response and IHC were assessed using Spearman rank order.
  
  
  RESULTS
  Of the 42 enrolled patients, 37 were evaluable. Adverse events were primarily transient, mild-to-moderate and infusion related. Patients developed T cell proliferation and interferon-γ responses detectable in the blood following treatment. Furthermore, a greater-than-three-fold increase in infiltrating CD3(+), CD4(+) FOXP3(-), and CD8(+) T cells was observed in the RP tissues compared with the pretreatment biopsy (binomial proportions: all P < .001). This level of T cell infiltration was observed at the tumor interface, and was not seen in a control group consisting of 12 concurrent patients who did not receive any neoadjuvant treatment prior to RP. The majority of infiltrating T cells were PD-1(+) and Ki-67(+), consistent with activated T cells. Importantly, the magnitude of the circulating immune response did not directly correlate with T cell infiltration within the prostate based upon Spearman's rank order correlation.
  
  
  CONCLUSIONS
  This study is the first to demonstrate a local immune effect from the administration of sipuleucel-T. Neoadjuvant sipuleucel-T elicits both a systemic antigen-specific T cell response and the recruitment of activated effector T cells into the prostate tumor microenvironment.
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA (LF, PC, VW, SC, JL, JS, EJS); Virginia Mason Medical Center, Seattle, WA (JC); Oregon Health & Science University, Portland, OR (CLA); University of Utah School of Medicine, Salt Lake City, UT (RAS); Dendreon Corporation, Seattle, WA (NAS, RBS, MWF). lfong@medicine.ucsf.edu.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Fong
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA (LF, PC, VW, SC, JL, JS, EJS); Virginia Mason Medical Center, Seattle, WA (JC); Oregon Health & Science University, Portland, OR (CLA); University of Utah School of Medicine, Salt Lake City, UT (RAS); Dendreon Corporation, Seattle, WA (NAS, RBS, MWF).
authors.forename: Peter
authors.initials: P
authors.lastname: Carroll
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA (LF, PC, VW, SC, JL, JS, EJS); Virginia Mason Medical Center, Seattle, WA (JC); Oregon Health & Science University, Portland, OR (CLA); University of Utah School of Medicine, Salt Lake City, UT (RAS); Dendreon Corporation, Seattle, WA (NAS, RBS, MWF).
authors.forename: Vivian
authors.initials: V
authors.lastname: Weinberg
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA (LF, PC, VW, SC, JL, JS, EJS); Virginia Mason Medical Center, Seattle, WA (JC); Oregon Health & Science University, Portland, OR (CLA); University of Utah School of Medicine, Salt Lake City, UT (RAS); Dendreon Corporation, Seattle, WA (NAS, RBS, MWF).
authors.forename: Stephen
authors.initials: S
authors.lastname: Chan
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA (LF, PC, VW, SC, JL, JS, EJS); Virginia Mason Medical Center, Seattle, WA (JC); Oregon Health & Science University, Portland, OR (CLA); University of Utah School of Medicine, Salt Lake City, UT (RAS); Dendreon Corporation, Seattle, WA (NAS, RBS, MWF).
authors.forename: Jera
authors.initials: J
authors.lastname: Lewis
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA (LF, PC, VW, SC, JL, JS, EJS); Virginia Mason Medical Center, Seattle, WA (JC); Oregon Health & Science University, Portland, OR (CLA); University of Utah School of Medicine, Salt Lake City, UT (RAS); Dendreon Corporation, Seattle, WA (NAS, RBS, MWF).
authors.forename: John
authors.initials: J
authors.lastname: Corman
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA (LF, PC, VW, SC, JL, JS, EJS); Virginia Mason Medical Center, Seattle, WA (JC); Oregon Health & Science University, Portland, OR (CLA); University of Utah School of Medicine, Salt Lake City, UT (RAS); Dendreon Corporation, Seattle, WA (NAS, RBS, MWF).
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Amling
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA (LF, PC, VW, SC, JL, JS, EJS); Virginia Mason Medical Center, Seattle, WA (JC); Oregon Health & Science University, Portland, OR (CLA); University of Utah School of Medicine, Salt Lake City, UT (RAS); Dendreon Corporation, Seattle, WA (NAS, RBS, MWF).
authors.forename: Robert A
authors.initials: RA
authors.lastname: Stephenson
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA (LF, PC, VW, SC, JL, JS, EJS); Virginia Mason Medical Center, Seattle, WA (JC); Oregon Health & Science University, Portland, OR (CLA); University of Utah School of Medicine, Salt Lake City, UT (RAS); Dendreon Corporation, Seattle, WA (NAS, RBS, MWF).
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Simko
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA (LF, PC, VW, SC, JL, JS, EJS); Virginia Mason Medical Center, Seattle, WA (JC); Oregon Health & Science University, Portland, OR (CLA); University of Utah School of Medicine, Salt Lake City, UT (RAS); Dendreon Corporation, Seattle, WA (NAS, RBS, MWF).
authors.forename: Nadeem A
authors.initials: NA
authors.lastname: Sheikh
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA (LF, PC, VW, SC, JL, JS, EJS); Virginia Mason Medical Center, Seattle, WA (JC); Oregon Health & Science University, Portland, OR (CLA); University of Utah School of Medicine, Salt Lake City, UT (RAS); Dendreon Corporation, Seattle, WA (NAS, RBS, MWF).
authors.forename: Robert B
authors.initials: RB
authors.lastname: Sims
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA (LF, PC, VW, SC, JL, JS, EJS); Virginia Mason Medical Center, Seattle, WA (JC); Oregon Health & Science University, Portland, OR (CLA); University of Utah School of Medicine, Salt Lake City, UT (RAS); Dendreon Corporation, Seattle, WA (NAS, RBS, MWF).
authors.forename: Mark W
authors.initials: MW
authors.lastname: Frohlich
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA (LF, PC, VW, SC, JL, JS, EJS); Virginia Mason Medical Center, Seattle, WA (JC); Oregon Health & Science University, Portland, OR (CLA); University of Utah School of Medicine, Salt Lake City, UT (RAS); Dendreon Corporation, Seattle, WA (NAS, RBS, MWF).
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Small
mesh_terms: D000368:Aged; D017252:CD3 Complex / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D051858:Forkhead Transcription Factors / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D011446:Prospective Studies; D011468:Prostatectomy / Q000379:methods; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology / Q000601:surgery; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014020:Tissue Extracts / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
chemical_list: D017252:CD3 Complex; D019496:Cancer Vaccines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D014020:Tissue Extracts; D007371:Interferon-gamma; C511774:sipuleucel-T