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: Lawrence Fong, Peter Carroll, Vivian Weinberg, Stephen Chan, Jera Lewis, John Corman, Christopher L Amling, Robert A Stephenson, Jeffrey Simko, Nadeem A Sheikh, Robert B Sims, Mark W Frohlich, Eric J Small
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 106 Issue 11 (Nov 2014) ISSN: 1460-2105 [Electronic] United States
• PMID: 25255802 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press.

Chemical References

• CD3 Complex
• Cancer Vaccines
• FOXP3 protein, human
• Forkhead Transcription Factors
• Tissue Extracts
• Interferon-gamma
• sipuleucel-T

Topics

• Aged
• CD3 Complex (drug effects)
• CD4-Positive T-Lymphocytes (drug effects)
• CD8-Positive T-Lymphocytes (drug effects)
• Cancer Vaccines (administration & dosage, adverse effects, therapeutic use)
• Forkhead Transcription Factors (drug effects)
• Humans
• Immunohistochemistry
• Immunotherapy (methods)
• Interferon-gamma (drug effects, immunology)
• Lymphocyte Activation (drug effects, immunology)
• Male
• Middle Aged
• Neoadjuvant Therapy (methods)
• Prospective Studies
• Prostatectomy (methods)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, immunology, pathology, surgery)
• T-Lymphocytes (drug effects, immunology)
• Tissue Extracts (administration & dosage, adverse effects, therapeutic use)
• Treatment Outcome
• Tumor Microenvironment (drug effects, immunology)