Sipuleucel-T: harbinger of a new age of therapeutics for prostate cancer.
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ABSTRACT:
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]
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Project description:Tumors evade the immune system though a myriad of mechanisms. Using checkpoint inhibitors to help reprime T cells to recognize tumor has had great success in malignancies including melanoma, lung, and renal cell carcinoma. Many tumors including prostate cancer are resistant to such treatment. However, Sipuleucel-T, a dendritic cell (DC) based immunotherapy, improved overall survival (OS) in prostate cancer. Despite this initial success, further DC vaccines have failed to progress and there has been limited uptake of Sipuleucel-T in the clinic. We know in prostate cancer (PCa) that both the adaptive and the innate arms of the immune system contribute to the immunosuppressive environment. This is at least in part due to dysfunction of DC that play a crucial role in the initiation of an immune response. We also know that there is a paucity of DC in PCa, and that those there are immature, creating a tolerogenic environment. These attributes make PCa a good candidate for a DC based immunotherapy. Ultimately, the knowledge gained by much research into antigen processing and presentation needs to translate from bench to bedside. In this review we will analyze why newer vaccine strategies using monocyte derived DC (MoDC) have failed to deliver clinical benefit, particularly in PCa, and highlight the emerging antigen loading and presentation technologies such as nanoparticles, antibody-antigen conjugates and virus co-delivery systems that can be used to improve efficacy. Lastly, we will assess combination strategies that can help overcome the immunosuppressive microenvironment of PCa.
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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.
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Project description:The effective treatment of castrate-resistant prostate cancer (CRPC) has proven to be very challenging. Until recently, docetaxel was the only therapeutic demonstrated to extend overall patient survival. Yet recently, a considerable number of new therapeutics have been approved to treat CRPC patients. These remarkable advances now give new tools for the therapeutic management of late-stage prostate cancer. In this review, we will examine mechanistic and clinical data of several newly approved therapeutics including the chemotherapeutic cabazitaxel, antiandrogen enzalutamide, endocrine disruptor abiraterone acetate, immunotherapy sipuleucel-T, and bone-targeting radiopharmaceutical alpharadin. In addition, we will examine other promising therapeutics that are currently in Phase III trials.
| S-EPMC3678432 | biostudies-literature
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.
| S-EPMC4523381 | biostudies-literature
Project description:Sipuleucel-T was approved by the US Food and Drug Administration on April 29, 2010, as an immunotherapy for late-stage prostate cancer. To manufacture sipuleucel-T, mononuclear cells harvested from the patient are incubated with a recombinant prostatic acid phosphatase (PAP) antigen and reinfused. The manufacturer proposes that antigen-presenting cells exogenously activated by PAP induce endogenous T-cells to attack PAP-bearing prostate cancer cells. However, the lack of demonstrable tumor responses has prompted calls for scrutiny of the design of the trials in which sipuleucel-T demonstrated a 4-month survival benefit. Previously unpublished data from the sipuleucel-T trials show worse overall survival in older vs younger patients in the placebo groups, which have not been shown previously to be prognostic for survival in castration-resistant prostate cancer patients receiving chemotherapy. Because two-thirds of the cells harvested from placebo patients, but not from the sipuleucel-T arm, were frozen and not reinfused, a detrimental effect of this large repeated cell loss provides a potential alternative explanation for the survival "benefit." Patient safety depends on adequately addressing this alternative explanation for the trial results.
| S-EPMC3283534 | biostudies-other
Project description:ContextProstate cancer remains highly prevalent and has a poor clinical outcome once metastatic. Sipuleucel-T is an autologous cellular immunotherapy approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T treatment extends survival but is independent of traditional short-term markers of treatment response observed with chemotherapy and contemporary hormonal treatments. Therefore, it is essential that clinicians understand the mechanism of action of sipuleucel-T and how this can translate in the clinic.ObjectiveThis article aims to summarize the current knowledge of sipuleucel-T therapy and its effects in mCRPC.Evidence acquisitionRelevant publications describing sipuleucel-T clinical data and information relating to immunotherapies were identified.Evidence synthesisTreatment with sipuleucel-T extends survival, with side effects being usually mild or moderate and manageable within the outpatient setting. The long-term immune responses generated by sipuleucel-T correlate with a survival benefit. Sipuleucel-T shows a greater magnitude of clinical benefit when used in patients earlier in the mCRPC setting.ConclusionsSipuleucel-T stimulates long-lived immune responses that translate into long-term clinical benefit. The treatment course (three infusions at weeks 0, 2, and 4) is associated with manageable side effects. Short-term markers of future benefit would be clinically useful, and information on effective treatment combinations or sequences is awaited. Sipuleucel-T treatment directs the patient's own immune system to target and remove prostate cancer cells and increases life expectancy. Patients whose cancer is less advanced generally have a more 'active' immune system and may benefit the most from this treatment.
| S-EPMC4456994 | biostudies-literature
Project description:Sipuleucel-T is an autologous cellular immunotherapy approved in the US for patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). This significant advance for mCRPC treatment provides healthcare professionals with another effective therapy to extend survival. As an immunotherapy, sipuleucel-T possesses specific characteristics differentiating it from traditional therapies. At a roundtable meeting of experts, sipuleucel-T data were discussed, focusing on interpretation and clinical implications. Important differences between immunotherapies and traditional therapies were explored, e.g., mode of action, outcomes, data consistency and robustness, timing of sipuleucel-T treatment, and future perspectives in areas such as short-term markers of long-term benefit.
| S-EPMC4839373 | biostudies-literature
Project description:Sipuleucel-T, an autologous cellular immunotherapy manufactured from antigen-presenting cells primed to recognize prostatic acid phosphatase, was the first immunotherapy product approved by the US FDA. It was approved for men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer after it was shown to provide a survival advantage. Additional studies have examined its use in other clinical settings and in combination with other approved and investigational immunotherapy agents. This review will discuss the pivotal trials leading to approval, will outline some of the biomarkers associated with its efficacy and will review some of the ongoing combination strategies. Maximizing the efficacy of sipuleucel-T through better patient selection or through combination approaches remains the challenge of the future.
| S-EPMC5925432 | biostudies-literature
Project description:T cell-mediated adaptive immune response is controlled by both positive costimulation and negative coinhibition, generated mainly by the interaction between the B7 family and their receptor CD28 family. Coinhibition is exploited by prostate cancer as an immune evasion pathway. Overexpression of coinhibitory B7x and B7-H3 in prostate cancer correlates with poor disease outcome, whereas tumor-infiltrating immune cells have enhanced expression of PD-L1 and its receptor PD-1. New insights into the complex mechanisms governing B7 expression in the tumor microenvironment have been reported and therapies aimed at overcoming T cell coinhibition with antagonistic monoclonal antibodies are emerging as effective tumor immunotherapies. Therapies that block B7x and B7-H3, either as monotherapies or in synergism with traditional therapies, should be pursued.
| S-EPMC3039708 | biostudies-literature
Project description:ImportanceSipuleucel-T is an immunotherapy that has been approved for use in patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). However, sipuleucel-T may not be available to some patients because of logistics, cost, and practice structure.ObjectiveTo identify factors associated with the adoption of sipuleucel-T across the United States.Design, setting, and participantsIn this retrospective cohort study, patients with prostate cancer who received therapy for mCRPC (docetaxel, abiraterone acetate, enzalutamide, cabazitaxel, radium 223, or sipuleucel-T) from January 1, 2010, through June 30, 2016, were identified in a large claims database of commercially insured patients. Patients who received sipuleucel-T were compared with patients who received any of the other treatments for mCRPC but did not receive sipuleucel-T. Data were analyzed from May 3, 2018, to February 24, 2019.ExposuresSipuleucel-T treatment.Main outcomes and measuresPatterns of treatment that involved the use of sipuleucel-T were elucidated, and binomial logistic regression was conducted to determine patient and physician factors that were associated with the use of sipuleucel-T and whether patients received sipuleucel-T in isolation or concurrently with other therapies.ResultsAmong 7272 patients who received a treatment for mCRPC, 730 (10.0%) received sipuleucel-T. Mean (SD) age of patients in the entire cohort was 73.2 (9.2) years; 6739 (92.7%) were non-Hispanic and 975 (13.4%) were black. In multivariable analysis, patients who were Hispanic (odds ratio [OR], 0.57; 95% CI, 0.38-0.86) or lived in the Pacific region (OR, 0.66; 95% CI, 0.45-0.97) had lower odds of receiving sipuleucel-T than patients who were not Hispanic or who lived in the South Atlantic region. Patients with higher incomes had greater odds of receiving sipuleucel-T than patients with incomes of less than $50?000 (OR, 1.29 [95% CI, 1.04-1.61] for $50?000-$99?000; OR, 1.43 [95% CI, 1.10-1.85] for >$99?000). Patients treated by a urologist had greater odds of receiving sipuleucel-T than patients not treated by a urologist (OR, 8.89; 95% CI, 7.10-11.11). Sixty-seven patients received concurrent therapies with sipuleucel-T, most commonly abiraterone or enzalutamide, but no factors were independently associated with patients receiving sipuleucel-T concurrent with other therapies for mCRPC.Conclusions and relevanceIn this study, 1 of 10 patients with prostate cancer who were treated for mCRPC received sipuleucel-T, with several variables associated with its use. Identifying disparities in receipt of sipuleucel-T may affect future access to this and other highly specialized cancer therapies by defining barriers to treatment that could be addressed in future studies.
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