Putting the Pieces Together: Completing the Mechanism of Action Jigsaw for Sipuleucel-T

Ravi A. Madan, Emmanuel S. Antonarakis, Charles G. Drake, Lawrence Fong, Evan Y. Yu, Douglas G. McNeel, Daniel W. Lin, Nancy N. Chang, Nadeem A. Sheikh, James L. Gulley

Research output: Contribution to journalReview articlepeer-review

11 Scopus citations


Sipuleucel-T is an autologous cellular immunotherapy that induces an immune response targeted against prostatic acid phosphatase (PAP) to treat asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. In the phase III IMPACT study, sipuleucel-T was associated with a statistically significantly increased overall survival (OS) (median = 4.1 months) vs placebo. Patients with baseline prostate-specific antigen levels in the lowest quartile (=22.1 ng/mL) exhibited a 13-month improvement in OS with sipuleucel-T. Together, this led sipuleucel-T to be approved and recommended as first-line therapy in various guidelines for treatment of metastatic castration-resistant prostate cancer. This review discusses the varied findings about the mechanisms of action of sipuleucel-T, bringing them together to form a more coherent picture. These pieces include inducing a statistically significant increase in antigen-presenting cell activation; inducing a peripheral immune response specific to the target (PAP) and/or immunizing (PA2024) antigens; stimulating systemic cytotoxic T-lymphocyte activity; and mediating antigen spread (ie, increased antibody responses to secondary proteins in addition to PAP and PA2024). Each of these pieces individually correlates with OS. Sipuleucel-T also traffics T cells to the prostate and is associated with long-term immune memory such that a second course of treatment induces an anamnestic immune response. Prostate cancer does not have a strongly inflamed microenvironment, thus its response to immune checkpoint inhibitors is limited. Because sipuleucel-T is able to traffic T cells to the tumor, it may be an ideal combination partner with immunotherapies including immune checkpoint inhibitors or with radiation therapy.

Original languageEnglish (US)
Article numberdjaa021
Pages (from-to)562-573
Number of pages12
JournalJournal of the National Cancer Institute
Issue number6
StatePublished - Jun 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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