Prostate Cancer Immunotherapy with Sipuleucel-T: Current Standards and Future Directions

Abstract

The management of advanced prostate cancer, specifically metastatic castrate-resistant prostate cancer (mCRPC), remains a therapeutic challenge. Sipuleucel-T (Provenge; APC8015) was approved by the FDA in 2010 for the treatment of asymptomatic or minimally symptomatic mCRPC patients, and it remains the only FDA-approved immunotherapy for prostate cancer of any indication to date. Given the continued need to improve therapeutics in patients with advanced prostate cancer, as well as recent enthusiasm for cancer immunotherapy, there is a wide range of ongoing trials evaluating combinations of sipuleucel-T with other therapeutics. Additional trials are aiming to expand the application of sipuleucel-T to prostate cancer patients beyond the mCRPC setting. Ongoing challenges include understanding the full mechanism of action of sipuleucel-T, optimizing the sequence of sipuleucel-T in relation to other therapies for mCRPC in clinical practice, and the identification of surrogate markers to predict survival benefit in clinical trials.

Keywords:

• cancer immunotherapy
• cancer vaccine
• GM-CSF
• PAP
• PA2024
• prostate cancer
• provenge
• sipuleucel-T

Key issues

• Sipuleucel-T is approved for the treatment of asymptomatic and minimally symptomatic mCRPC patients based on its overall survival benefit, but surrogate endpoints to predict survival benefit need to be elucidated.

• Sipuleucel-T appears to have the most clinical benefit in patients with lower disease burden, as supported by data that a lower pretreatment PSA is the strongest independent prognostic factor for improved survival. However, this observation has not been validated in prospective trials, and hence is only hypothesis generating at this time.

• The mechanism of action of sipuleucel-T may extend beyond T cell-mediated recognition and targeting of PAP-expressing prostate cancer cells, and the active component in the sipuleucel-T product may include immune cells other than CD54+ APCs.

• Antigen-specific immune responses to PA2024 and/or PAP, as well as antigen spread and IgG responses to PSA and LGALS3, have been associated with improved overall survival in patients receiving sipuleucel-T. These immunomonitoring biomarkers need to be validated.

• Combinations of sipuleucel-T with ADT or abiraterone appear to be well tolerated in early-phase clinical trials without blunting of immunologic effects. Whether these combinations increase the clinical efficacy of sipuleucel-T remains to be determined.

• Multiple ongoing clinical trials are investigating the combination of sipuleucel-T with other therapies that may have immunomodulatory effects, including hormonal agents, radiation therapies and immune checkpoint antibodies.

Financial and competing interests disclosure

L Fong has received research support from Dendreon. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

ORCID

Lawrence Fong http://orcid.org/0000-0002-6428-428X