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Sipuleucel-T: harbinger of a new age of therapeutics for prostate cancer.

ABSTRACT: Sipuleucel-T (Provenge) is the first therapeutic cancer vaccine approved by the US FDA. The approval heralds the long-awaited promise of improved patient survival with minimal toxicity by therapies designed to generate an active, specific anticancer immune response. The development of this first-in-class agent as well as other therapeutic vaccines in clinical evaluation has also led to a better understanding of relevant patient populations and end points for clinical trials. This article discusses the development and approval of sipuleucel-T in the context of other approved therapies for prostate cancer, as well as controversies and novel paradigms brought about by this new agent.

SUBMITTER: Madan RA

PROVIDER: S-EPMC3460263 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Sipuleucel-T: harbinger of a new age of therapeutics for prostate cancer.

Madan Ravi A RA Gulley James L JL

Expert review of vaccines 20110201 2

Sipuleucel-T (Provenge) is the first therapeutic cancer vaccine approved by the US FDA. The approval heralds the long-awaited promise of improved patient survival with minimal toxicity by therapies designed to generate an active, specific anticancer immune response. The development of this first-in-class agent as well as other therapeutic vaccines in clinical evaluation has also led to a better understanding of relevant patient populations and end points for clinical trials. This article discuss ...[more]

PMID: 21332262

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Project description:Historically, chemotherapy has remained the most commonly utilized therapy in patients with metastatic cancers. In prostate cancer, chemotherapy has been reserved for patients whose metastatic disease becomes resistant to first line castration or androgen deprivation. While chemotherapy palliates, decreases serum prostate specific antigen and improves survival, it is associated with significant side effects and is only suitable for approximately 60% of patients with castrate-resistant prostate cancer. On that basis, exploration of other therapeutic options such as active secondary hormone therapy, bone targeted treatments and immunotherapy are important. Until recently, immunotherapy has had no role in the treatment of solid malignancies aside from renal cancer and melanoma. The FDA-approved autologous cellular immunotherapy sipuleucel-T has demonstrated efficacy in improving overall survival in patients with metastatic castrate-resistant prostate cancer in randomized clinical trials. The proposed mechanism of action is reliant on activating the patients' own antigen presenting cells (APCs) to prostatic acid phosphatase (PAP) fused with granulocyte-macrophage colony stimulating factor (GM-CSF) and subsequent triggered T-cell response to PAP on the surface of prostate cancer cells in the patients body. Despite significant prolongation of survival in Phase III trials, the challenge to health care providers remains the dissociation between objective changes in serum PSA or on imaging studies after sipleucel-T and survival benefit. On that basis there is an unmet need for markers of outcome and a quest to identify immunologic or clinical surrogates to fill this role. This review focuses on the impact of sipuleucel-T on the immune system, the T and B cells, and their responses to relevant antigens and prostate cancer. Other therapeutic modalities such as chemotherapy, corticosteroids and GM-CSF and host factors can also affect immune response. The optimal timing for immunotherapy, patient selection and best sequencing with other prostate cancer therapies remain to be determined. A better understanding of immune response may help address these issues.

Project description:Opinion statementAt present, sipuleucel-T represents the only approved immunotherapy for prostate cancer. Sipuleucel-T is an autologous cellular therapy, which primes autologous antigen-presenting cells against the prostatic acid phosphatase (PAP) antigen. For patients with metastatic castrate-resistant prostate cancer (CRPC) who are asymptomatic or minimally symptomatic, sipuleucel-T monotherapy is one of the standard of care treatment options pre- or postdocetaxel. With the approval of new treatments, including abiraterone and enzatutamide, sequencing and combination of these treatments with sipuleucel-T represent unanswered questions facing the field. Whereas steroids that are coadministered with abiraterone and chemotherapy have long been thought to be immunosuppressive, early results show that concurrent abiraterone and prednisone does not significantly impact the ability to develop immune responses to this treatment. Additional clinical data are needed to elucidate optimal sequencing of therapeutic agents in CRPC. Several novel immunotherapies are currently in development, and enrollment in clinical trials should be considered. These include PROSTVAC-VF, a viral vaccine that encodes PSA and T-cell costimulatory molecules, which is currently undergoing phase III clinical trials. DNA plasmid-based vaccines targeting different antigens, including PAP, also are under investigation. Immune checkpoint blockade with ipilimumab, a monoclonal antibody against CTLA-4, which is approved for metastatic melanoma, also is being evaluated. Whereas this treatment failed to show significant improvement in overall survival in CRPC patients treated with docetaxel, results from a phase III trial in the predocetaxel setting are pending. Conventional therapies for prostate cancer, such as radiation and hormonal therapy, may have immunomodulatory effects. Future areas for research include the sequencing and combination of immunotherapies as well as other conventional therapies.

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Sipuleucel-T: harbinger of a new age of therapeutics for prostate cancer.

Publications

Sipuleucel-T: harbinger of a new age of therapeutics for prostate cancer.

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