Activated lymphocyte recruitment into the tumor microenvironment following preoperative sipuleucel-T for localized prostate cancer

Lawrence Fong, Peter Carroll, Vivian Weinberg, Stephen Chan, Jera Lewis, John Corman, Christopher Amling, Robert A. Stephenson, Jeffrey Simko, Nadeem A. Sheikh, Robert B. Sims, Mark W. Frohlich, Eric J. Small

Research output: Contribution to journalArticle

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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 + 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.

Original languageEnglish (US)
Article numberdju268
JournalJournal of the National Cancer Institute
Volume106
Issue number11
DOIs
StatePublished - Nov 1 2014

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Tumor Microenvironment
Prostatic Neoplasms
Lymphocytes
T-Lymphocytes
Prostatectomy
Prostate
Immunohistochemistry
Biopsy
Castration
United States Food and Drug Administration
Immunotherapy
Interferons
sipuleucel-T
Cell Proliferation
Antigens

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Activated lymphocyte recruitment into the tumor microenvironment following preoperative sipuleucel-T for localized prostate cancer. / Fong, Lawrence; Carroll, Peter; Weinberg, Vivian; Chan, Stephen; Lewis, Jera; Corman, John; Amling, Christopher; Stephenson, Robert A.; Simko, Jeffrey; Sheikh, Nadeem A.; Sims, Robert B.; Frohlich, Mark W.; Small, Eric J.

In: Journal of the National Cancer Institute, Vol. 106, No. 11, dju268, 01.11.2014.

Research output: Contribution to journalArticle

Fong, L, Carroll, P, Weinberg, V, Chan, S, Lewis, J, Corman, J, Amling, C, Stephenson, RA, Simko, J, Sheikh, NA, Sims, RB, Frohlich, MW & Small, EJ 2014, 'Activated lymphocyte recruitment into the tumor microenvironment following preoperative sipuleucel-T for localized prostate cancer', Journal of the National Cancer Institute, vol. 106, no. 11, dju268. https://doi.org/10.1093/jnci/dju268
Fong, Lawrence ; Carroll, Peter ; Weinberg, Vivian ; Chan, Stephen ; Lewis, Jera ; Corman, John ; Amling, Christopher ; Stephenson, Robert A. ; Simko, Jeffrey ; Sheikh, Nadeem A. ; Sims, Robert B. ; Frohlich, Mark W. ; Small, Eric J. / Activated lymphocyte recruitment into the tumor microenvironment following preoperative sipuleucel-T for localized prostate cancer. In: Journal of the National Cancer Institute. 2014 ; Vol. 106, No. 11.
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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 + 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.",
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AU - Fong, Lawrence

AU - Carroll, Peter

AU - Weinberg, Vivian

AU - Chan, Stephen

AU - Lewis, Jera

AU - Corman, John

AU - Amling, Christopher

AU - Stephenson, Robert A.

AU - Simko, Jeffrey

AU - Sheikh, Nadeem A.

AU - Sims, Robert B.

AU - Frohlich, Mark W.

AU - Small, Eric J.

PY - 2014/11/1

Y1 - 2014/11/1

N2 - 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 + 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.

AB - 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 + 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.

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