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

43 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
Externally publishedYes

Bibliographical note

Funding Information:
This work was funded by Dendreon Pharmaceuticals LLC, including both provision of medical writing support and sponsoring many of the sipuleucel-T studies described herein.

Funding Information:
Medical writing assistance, in the form of developing the draft outline and manuscript first draft in consultation with the authors, revising draft versions, assembling tables and figures, collating author comments, copy editing, fact checking, referencing, and providing graphic services was provided by Catherine Lee and Jackie Phillipson of Zoetic Science (Macclesfield, UK), which was funded by Dendreon Pharmaceuticals LLC. Additional medical writing support was provided by Helen M. Wilfehrt, PhD, CMPP, of Dendreon Pharmaceuticals LLC.

Funding Information:
ESSA; and grants from Johnson & Johnson, Genentech, Novartis, Bristol Myers-Squibb, Tokai, and Celgene, outside the submitted work. Dr Drake reports consulting fees from Bristol Myers Squibb, Brooklyn Therapeutics, Compugen, EMD Serono, F-Star, Ferring, Genocea, Harpoon, Kleo, Merck, Pfizer, Roche-Genentech, Sanofi Aventis, Shattuck Labs, Tizona, and Werewolf, as well as equity interest in Compugen, Harpoon, Kleo, Tizona, and Werewolf. Dr Fong reports grants from Dendreon, Abbvie, Bavarian Nordic, BMS, Janssen, Merck, and Roche/Genentech during the conduct of the study. Dr Yu reports personal fees from Amgen, Clovis, Astrazeneca, Janssen, Pharmacyclics, QED, Tolmar, Incyte, EMD Serono, and Churchill; and grants and personal fees from Bayer, Dendreon, Merck, Seattle Genetics, outside the submitted work. Dr McNeel reports grants, personal fees, and other from Madison Vaccines, Inc; other from Janssen Pharmaceuticals and Novartis; nonfinancial support from BMS; and grants and other from Merck, outside the submitted work. In addition, Dr McNeel has several patents related to vaccines for prostate cancer, none specific to sipuleucel-T, licensed to Madison Vaccines, Inc. Dr Lin has nothing to disclose. Dr Chang reports other from Dendreon, outside the submitted work. She was an employee of Dendreon Pharmaceuticals LLC, makers of sipuleucel-T, when this manuscript was written. Dr Sheikh reports other from Dendreon Pharmaceuticals, outside the submitted work. Dr Sheikh is a current employee of Dendreon Pharmaceuticals LLC, makers of sipuleucel-T. In addition, Dr Sheikh has a patent “Humoral Immune Response Against Tumor Antigens After Treatment With a Cancer Antigen Specific Active Immunotherapy and Its Association With Improved Clinical Outcome,” issued and a patent, “Gene Expression Markers for Predicting Overall Survival in Subjects Treated With Sipuleucel-T,” pending. Dr Gulley has nothing to disclose.

Publisher Copyright:
© 2020 The Author(s) 2020. Published by Oxford University Press.


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