治疗性癌症疫苗Provenge

最近Dendreon公司完成了在美国递交其治疗性癌症疫苗产品Provenge（sipuleucel—T）的上市申请事宜，该产品将成为首个在美国获准的治疗性癌症疫苗，用于治疗转移型激素难治性晚期前列腺癌。在2007年5月，美国FDA曾拒绝批准该产品的申报，要求补充其IMPACT临床试验中受试者的生存期数据，     

Current paradigms and evolving concepts in metastatic castration-resistant prostate cancer

Until recently, docetaxel-based therapy represented the only therapy shown to prolong survival in patients with metastatic castration-resistant prostate cancer (mCRPC). The past year and a half has been marked by unprecedented progress in treatments for this disease. Three positive phase III clinical trials have emerged, each evaluating agents (sipuleucel-T, cabazitaxel and abiraterone) with distinct mechanisms of action. Herein, the three pivotal trials are described alongside both past and current large phase III studies conducted in this mCRPC. The overall survival for patients with mCRPC treated in current clinical trials is considerably longer than noted in the past. We note that more recent trials with older agents have also shown improved survival and discuss potential non-therapeutic biases that influence this critical measure of outcome. The necessity for utilizing randomized trials when evaluating new therapeutics is emphasized given the changing prognosis in this mCRPC.     

Clinical Variables Associated With Overall Survival in Metastatic Castration-Resistant Prostate Cancer Patients Treated With Sipuleucel-T Immunotherapy

Background

Sipuleucel-T is an autologous cell-based cancer immunotherapy for men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Its approval by the Food and Drug Administration was based on demonstration of an overall survival (OS) benefit in randomized placebo-controlled phase III trials. However, treatment was associated with a prostate-specific antigen (PSA) decline in only a small minority of patients. Understanding the clinical factors that are associated with OS could help guide treatment decisions, including patient selection and the timing of sipuleucel-T relative to other therapies.

Sipuleucel-T immunotherapy for castration-resistant prostate cancer. A systematic review and meta-analysis

Introduction

Sipuleucel-T is a novel active cellular immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC). It is assumed to be associated with less adverse events than conventional docetaxel-based chemotherapy.

Material and methods

A systematic review of literature published between January, 1 1966 and February, 6 2012 was performed to assess the efficacy and safety of sipuleucel-T in patients with mCRPC. Databases were searched: Medline, EMBASE, Cochrane, CancerLit as well as ASCO and ESCO websites.

Results

Three randomized clinical trials with a total of 737 participants fulfilled established criteria. The overall survival of patients who received sipuleucel-T in comparison to the control group was significantly longer with a hazard ratio (HR) of 0.73 (95% CI: 0.61-0.88; p = 0.001). Time to disease progression was not prolonged using sipuleucel-T compared to placebo, HR = 0.89 (95% CI: 0.75-1.05; p = 0.18). Relative benefit (RB) of serum PSA level reduction of at least 50% for sipuleucel-T compared to placebo did not meet statistical significance, RB = 1.97 (95% CI: 0.48-8.14; p = 0.38). The safety population consisted of 729 patients with mCRPC. Compared to the control group, the pooled relative risks (RR) of all adverse events – RR = 1.03 (95% CI: 1.00-1.05; p = 0.06), grade 3 to 5 adverse events – RR = 0.98 (95% CI: 0.79-1.22; p = 0.86) and cerebrovascular events – RR = 1.93 (95% CI: 0.73-5.09; p = 0.18) were not significantly higher for men treated with sipuleucel-T.

Conclusions

The use of sipuleucel-T prolonged the overall survival among men with mCRPC. No effect on time to disease progression was observed and the safety profile was acceptable.     

Immunotherapy with autologous antigen presenting cells for the treatment of androgen independent prostate cancer

Prostate cancer is an excellent target for an active vaccine-based approach based on the fact that prostate cancer cells express unique proteins which serve as highly specific targets. APC8015 (Provenge) is one such investigational therapeutic vaccine that uses autologous antigen presenting cells (APCs) loaded with a recombinant fusion protein of prostatic acid phosphatase linked to a molecule that specifically targets a receptor expressed on the surface of human APCs. Clinical trial outcomes have demonstrated activity in patients with androgen independent prostate cancer.     

Immunotherapy for metastatic prostate cancer: where are we at with sipuleucel-T?

Importance of the field: Prostate cancer is the leading malignancy in North American men and despite improvements in treatments 20 – 30% of patients will relapse. Immunotherapy using activated mononuclear cells is a way to harness the body's adaptive immune response to fight metastatic prostate cancer.

Areas covered in this review: In 2005, at least 10 therapeutic cancer vaccines, designed to confer active, specific immunotherapy against tumor-associated antigens, were in clinical trials. These covered potential fields of immunological strategy to overcome castration-resistant prostate cancer.

What the reader will gain: A literature review was performed using the search terms sipuleucel-T, Provenge and APC8015 or APC-8015, and restricted to English language articles from 2000 to 2010. The immunological design and development of sipuleucel-T are summarized. The efficacy and safety of sipuleucel-T are discussed based on current data from clinical trials. Ongoing clinical trials involving sipuleucel-T are summarized.

Take home message: Efficacy and safety with sipuleucel-T has been demonstrated in Phase I/II trials. The latest data from a Phase III trial shows that sipuleucel-T has met the primary endpoint of survival benefit. Further work is needed to understand the mechanisms behind cancer vaccine failure and elucidate the population for whom this vaccine will be suitable.     

Integrated data from 2 randomized,double‐blind,placebo‐controlled,phase 3 trials of active cellular immunotherapy with sipuleucel‐T in advanced prostate cancer

BACKGROUND:

Sipuleucel‐T is an investigational active cellular immunotherapy product designed to stimulate an immune response against prostate cancer. The safety and efficacy of sipuleucel‐T was evaluated in 2 identically designed, randomized, double‐blind, placebo‐controlled trials (D9901 and D9902A) conducted in men with advanced prostate cancer.

METHODS:

A total of 225 patients were randomized in D9901 or D9902A to sipuleucel‐T (n = 147) or placebo (n = 78), given as 3 intravenous infusions approximately 2 weeks apart. Patients were followed for survival until death or a prespecified cutoff of 36 months after randomization.

RESULTS:

In the integrated analysis of D9901 and D9902A, patients randomized to sipuleucel‐T demonstrated a 33% reduction in the risk of death (hazard ratio, 1.50; 95% confidence interval, 1.10‐2.05; P = .011; log‐rank). The treatment effect remained strong after performing adjustments for imbalances in baseline prognostic factors, poststudy treatment chemotherapy use, and non–prostate cancer‐related deaths. Additional support for the activity of sipuleucel‐T is provided by the correlation between a measure of the product's potency, CD54 up‐regulation, and overall survival. The most common adverse events associated with treatment were chills, pyrexia, headache, asthenia, dyspnea, vomiting, and tremor. These events were primarily grade 1 and 2, with durations of 1 to 2 days.

CONCLUSIONS:

The integrated results of D9901 and D9902A demonstrate a survival benefit for patients treated with sipuleucel‐T compared with those treated with placebo. The generally modest toxicity profile, coupled with the survival benefit, suggests a favorable risk‐benefit ratio for sipuleucel‐T in patients with advanced prostate cancer. Cancer 2009. © 2009 American Cancer Society.     

Immunotherapy for prostate cancer using antigen-loaded antigen-presenting cells: APC8015 (Provenge®)

Dendritic cells are deficient both in number and function in patients with cancer. Loaded dendritic cell therapies aim to overcome this deficiency by delivering antigens to antigen-presenting cells under ex vivo conditions, improving dendritic cell function. APC8015 (Provenge^®; Dendreon Corp., Seattle, WA) is a novel immunotherapeutic, which consists of autologous dendritic cells pulsed ex vivo with PA2024, a recombinant fusion protein consisting of granulocyte macrophage colony-stimulating factor and prostatic acid phosphatase, as an immunogenic agent. A Phase III randomized clinical trial has demonstrated a survival benefit in patients with metastatic hormone-refractory prostate cancer. This review summarizes the clinical trials using APC8015 in prostate cancer and discusses its future role in the treatment of prostate cancer.     

肿瘤疫苗Provenge可延长前列腺癌患者的生存期

据报道,Dendrenon公司在2009年4月28日举办的美国泌尿协会(American Urological Association)年会上公布了一项名为IMPACT、由512名转移性雄激素非依赖性前列腺癌病人参加的随机、双盲、安慰剂对照Ⅲ期临床研究结果,其数据表明,该公司开发的新型肿瘤疫苗Provenge(sipuleucel-T)可延长此病患者的总体生存率.