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Beyond the Abstract - Development of novel immune interventions for prostate cancer, by Neeraj Agarwal and Nicholas J. Vogelzang

BERKELEY, CA (UroToday.com) - Prostate cancer is the leading cause of cancer related morbidity and mortality in men in the western world.

FDA approval of sipuleucel-T, an autologous dendritic cell based vaccine for the treatment of metastatic castration refractory prostate cancer (mCRPC), represents a significant advancement in the field of cancer vaccines. This update follows “Development of novel immune interventions for prostate cancer”[1] which focused on recent developments in the field of immunotherapy in prostate cancer. This review examines recent evidence for the use of sipuleucel-T, the first cancer vaccine approved by the FDA.

 

bta agarwalSipuleucel-T (Provenge®, Dendreon Corp, WA) consists of autologous APCs enriched for a CD54+ DC fraction, harvested by leukopheresis and cultured with a fusion protein (PA2024) comprising of prostate acid phosphatase (PAP) and granulocyte-monocyte colony stimulating factor (GM-CSF).[2] In a phase 3 trial (The IMPACT trial), 512 men with asymptomatic chemo-naive mCRPC, were randomized in a 2:1 ratio to sipuleucel-T (n=341) or placebo(n= 171).[2] The primary and secondary endpoints of the IMPACT trial were overall survival (OS) and progression free survival (PFS), respectively. The median OS was significantly improved in the sipuleucel-T group, when compared with placebo group (25.8 months vs. 21.7 months, hazard ratio, 0.77; p = 0.02), with a relative reduction of 22% in the risk of death in the sipuleucel-T group (hazard ratio 0.78; p = 0.03). Notably, response rates and PFS were similar in the two study groups. This may be attributed to the time delay in the translation of immunologic effects to clinically measurable anti-tumor effects seen with immunotherapy, resulting in initial progression followed by delayed reduction of tumor growth. Majority of adverse events were mild to moderate and included chills, fever, fatigue, nausea, and headache.

It is noteworthy that patients in the control arm of the IMPACT study who experienced disease progression were eligible to cross over to a nonrandomized open-label protocol to receive an investigational autologous immunotherapy made from cryopreserved cells (APC8015F). Of 171 patients in the control arm, 109 (64%) eventually received APC8015F upon disease progression. In an exploratory analysis, a rank-preserving structural failure time (RPSFT) model was used to estimate the OS benefit of sipuleucel-T after adjusting for a positive effect of APC8015F.[3] This method reduces the observed survival time after initiation of APC8015F in patients who crossed over, and iteratively performs this analysis until the overall sipuleucel-T treatment effect converges. After adjusting for the effect of APC8015F, and assuming that APC8015F was as effective as sipuleucel-T, the estimated OS benefit with sipuleucel-T was 7.8 months.

Two other smaller randomized trials, D9901 and D9902A, evaluating sipuleucel-T in mCRPC, reported results similar to those in the IMPACT study.[4] In a recently reported subgroup analysis of these three phase 3 trials, the effect of sipuleucel-T was determined in African American men enrolled in these trials (sipuleucel-T n=33; control n=10).[5] While no definitive conclusions should be drawn given the limited sample size, median OS in sipuleucel-T arm was 45.3 months compared with 14.6 months in control patients (HR=0.288; 95% CI: 0.125–0.662; p=0.003), a 30.7-month difference.

In the IMPACT study, antibody response against the immunizing antigen PA2024 was observed in 66% of patients in the sipuleucel-T group and 3% in the placebo group. While both T-cell and antibody responses to sipuleucel-T were observed; only antibody responses were associated with an improved OS. Furthermore, a transient increase in eosinophil counts was observed in 26.3% of patients in the sipuleucel-T arm at week 6 compared to 0.7% of control patients, returning to baseline by week 14. This was associated with an increased immune response, increased levels of Th2-type cytokines, and prolonged survival.[6] Similar results were seen in a recently reported pooled analysis of all three phase 3 trials of sipuleucel-T in mCRPC.[7] In univariate analyses, eosinophilia correlated with increased antigen-specific humoral response, increased levels of Th2-type cytokine production, an improved OS (p=0.057), an improved prostate cancer specific survival (p=0.031), and increased infusion-related adverse events.[8]

In the IMPACT trial, the survival benefit of sipuleucel-T was observed consistently across the subgroup of patients, including those with adverse prognostic factors, such as increased levels of PSA, lactate dehydrogenase, and alkaline phosphatase, as well as increased number of bone metastases, increased Gleason score, decreased performance status, and the presence of pain.[2] Baseline PSA showed a strong prognostic value with a trend toward greater treatment effect with sipuleucel-T in patients with baseline PSA below vs. above the median (HR=0.685 vs 0.865).[2] In an exploratory analysis, significance of baseline PSA as a predictor of treatment response was examined.[8] Baseline PSA (in ng/ml) was divided in to quartiles (≤22.1, >22.1 to 50.1, 50.1 to 134.1, and >134.1), and consistency of response within each quartile was assessed. The greatest magnitude of benefit with sipuleucel-T was observed in patients in the lowest PSA quartile, where median OS for sipuleucel-T vs. control was 41.3 vs. 28.3 months (HR=0.51 [95% CI: 0.31–0.85]), a 13.0-month improvement in OS. In contrast, the median OS for sipuleucel-T vs. control in the highest PSA quartile was 18.4 vs. 15.6 months (HR=0.84 [95% CI: 0.55–1.29]), i.e. only 2.8-month improvement in OS. In general, sipuleucel-T therapy was effective in all patient subgroups evaluated, with a trend towards a superior outcome in patients with baseline prognostic features indicative of less advanced disease, thus providing a rationale for administration of sipuleucel-T as early as possible.

To date, studies of sipuleucel-T in patients with mCRPC have focused on peripheral blood immune response, but none have evaluated the modulation of tumor infiltrating lymphocytes in the prostate microenvironment. In a recently reported neoadjuvant phase 2 study, sipuleucel-T was administered prior to radical prostatectomy to patients with localized prostate cancer.[9] Robust immune activation was reported, with increased frequency of T-cells (total T cells, as well as T helper cells, cytotoxic T cells, and T regulatory cells) at the interface between prostate cancer tissue and normal tissue. These data demonstrate the potential for sipuleucel-T to modulate the presence of lymphocytes at the tumor site. Several other trials of sipuleucel-T are underway or have been completed in various settings of prostate cancer with results expected in near future.

References:

  1. Agarwal N, Padmanabh S, Vogelzang NJ. Development of novel immune interventions for prostate cancer. Clin Genitourin Cancer, 10(2), 84-92 (2012).
  2. Kantoff PW, Higano CS, Shore ND et al. Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer. New England Journal of Medicine, 363(5), 411-422 (2010).
  3. Gomella L, G, Nabhan, C, DeVries,T, Whitmore,J,B, Frohlich, M,W, George, D,J. Estimating the overall survival benefit of sipuleucel-T in the IMPACT trial accounting for crossover treatment in control subjects with autologous immunotherapy generated from cryopreserved cells. AUA 2012. Abstract #683., (2012).
  4. Higano CS, Schellhammer PF, Small EJ et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer, 115(16), 3670-3679 (2009).
  5. McLeod D, G, Quinn, D,I, Cullen, J, Whitmore,J,B. Sipuleucel-T in African-Americans: a subgroup analysis of three Phase 3 studies of sipuleucel-T in metastatic castrate-resistant prostate cancer. AUA 2012. Abstract #953., (2012).
  6. Sims RB, Lin LRC, dela Rosa CP, Sheikh NA, Whitmore JB, Frohlich MW. Elevated Eosinophils Following Treatment with Sipuleucel-T In Men with Prostate Cancer Is Associated with Antigen-Specific Immune Response and Prolonged Survival. ASH Annual Meeting Abstracts, 116(21), 1491- (2010).
  7. McNeel D, G, Lin,D,W, Gardner,T, Sheikh,N,A, Whitmore,J,B, Sims,R,B, Dreicer, R. Correlation of increased eosinophil count following sipuleucel-T treatment with outcome in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC). J Clin Oncol 30, (suppl; abstr 4650) (2012).
  8. Chodak G, Schellhammer,P,F, Whitmore,J,B, Sims,R,B, Kantoff,P.W. Overall survival (OS) benefit with sipuleucel-T by baseline PSA: An exploratory analysis from the phase III IMPACT trial. J Clin Oncol 30, (suppl; abstr 4648) (2012).
  9. Fong L, Weinberg,V, Chan,S, Corman,J, Amling,C,L, Stevenson,R,A, Simko,J, Sims, R,B, Carroll,P, Small, E,J. Neoadjuvant sipuleucel-T in localized prostate cancer: Effects on immune cells within the prostate tumor microenvironment. J Clin Oncol 30, (suppl; abstr 2564) (2012).

 

 

Written by:
Neeraj Agarwal,a and Nicholas J. Vogelzangb as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract. 

  1. Huntsman Cancer Institute at the University of Utah, Salt Lake City, Utah, USA;
  2. US Oncology Research, Comprehensive Cancer Centers, Nevada, USA

Contact Details:
Neeraj Agarwal: Assistant Professor of Medicine, Department of Internal Medicine, Huntsman Cancer Institute at the University of Utah, Salt Lake City, 2000 Circle of hope, Ste 2123, Utah, 84117. Phone: 801-585-0255, Fax: 801-585-0124. Email:  .

Nicholas J. Vogelzang (corresponding author): Chair and Medical Director, Developmental Therapeutics and Member GU Committee, US Oncology Research, Comprehensive Cancer Centers, NV. 3730 S. Eastern Ave. Las Vegas, NV 89169. Tel.(702) 952-3400 (w), Fax.(702) 343-4397. Email:  .

 

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