Analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer indicates sipuleucel-T immune parameters correlate with survival, "Beyond the Abstract," by Mayer N. Fishman, MD, PhD, et al

BERKELEY, CA (UroToday.com) - Sipuleucel-T, an autologous cellular immunotherapy, was approved by the US FDA in 2010 with the indication for use in men with metastatic castrate-refractory prostate cancer with the clinically defined disease parameters of minimal or absent symptoms of metastasis. It uses three tandem cycles of leukapheresis, ex vivo loading and activation with the proprietary antigenic stimulator construct, PAP/GM-CSF (PA2024; prostatic acid phosphatase/granulocyte monocyte colony stimulating factor protein), and reinfusion of a cellular product. That product had a mix of lymphocytes (median values of lymphocyte populations: 62.3% CD3+ T cells; 11.0% CD56+ NK cells; 4.7% CD 19+ B cells) and antigen presenting cells (APC; 18.3%).[1] The present report [1] authored by Sheikh, and other colleagues from Dendreon, and Drs. Petrylak and Kantoff, presents details beyond the described antibodies and T-cell titers that were emphasized in the pivotal trial publication, reported by Kantoff, et al.[2]

"The role of autologous cellular immunotherapy is new, and it is one that will continue to evolve in its application in the clinic."

Common patterns comparing sipuleucel-T treated patients to the control arm were observed across three randomized trials [2, 3, 4] of similar designs: Improved overall survival (OS), but absence of two clinical parameters considered usual secondary endpoints among prostate cancer therapeutics trials, PSA decrements and increments of radiologic progression-free survival. These are mathematically and clinically secondary to OS differences, but the question persists about how the immune treatment mediates the anticancer effect to cause the survival improvement.

A controversial perspective on the cause of the OS differences observed in those randomized trials was described by Huber, et al., [5] and suggested that the design of the control arm was one in which a survival decrement was consequent to the leukapheresis step. This hypothesis has been refuted by several researchers,[6, 7, 8] and additional details of post-treatment immunologic events that improve the mechanistic understanding of sipuleucel-T could further disprove this viewpoint. Interestingly, however, the hypothesis by Huber et al. does support the concept of developing immunologic treatments for prostate cancer, as it underscores the relevance of leukocyte behavior for understanding and influencing prostate cancer growth patterns and a relationship to clinical outcomes.

Sheikh, et al.[1] present assays on cytokines and cells, aggregated from specimens from the leukapheresis and the processed product in the three trials.[2, 3, 4] Measured at the 0-, 2-, and 4-week time points, the antigen specific T cell responses to PA-2024 were statistically significantly increased, while responses to PAP were of lower magnitude, and did not meet statistical significance. Fifteen cytokines measured from the supernatant of the product (assayed at the same time points) demonstrated significant increases as compared to absent changes in the serial specimens from the control group. This reflects APC activation in some cases (such as IL-1β, or IL-8) or lymphocyte activation in other cases (such as IL-2 or interferon-γ). The lymphocyte activation markers more often showed a pattern of increase from week 0 to week 2, and then further from week 2 to week 4, consistent with the concept of an amplification mediated by the tandem re-infusion design.

As a next step, the OS experience is depicted in Kaplan-Meier curves comparing the subsets above, versus below, the median for APC activation, for APC count, and for total nucleated cell count in the processed product. Again, there is a statistically significant superiority for survival for the subset with the higher immunologically defined parameter. Similarly, the survival curves among those with a measured lymphocyte-type response (antibody or T-cell; to PA-2024 or to PAP) are seen to be well separated, statistically significantly better than those without such a response. The authors acknowledge analytic limitations that included “availability of immune response data for only a subset of patients, and the post hoc correlative nature of the analyses.”[1] Additionally, they note that “correlations between immune parameters and increased OS could result from healthier subjects with an improved probability of survival being more likely to generate robust immune responses.”[1]

If we knew for whom the immunologic features were optimal, that could be a way to change patient selection or cell processing -- defined with respect to immunologic parameters, not just clinical features. This could lead to a sipuleucel-T type treatment with a clinical impact that would be larger and more predictable. These assays on secondary endpoints of immune parameters have a common interpretation: The immune system has observable changes caused by sipuleucel-T infusions. The important take-home message from the present study is that subsets defined on the basis of specific immunologic assays have better survival. A converse implication of the present study is that it suggests a way to define (again, immunologically) a population at low likelihood of a clinically significant, favorable sipuleucel-T response. In the context of the high manufacturing costs, there is much interest to find ways to define for whom alternate therapeutic approaches to castrate-resistant prostate cancer may be better suited.

Sheikh, et al., and many others’ perspectives aim to connect the immune changes with specific clinical improvement. This report contributes to meeting the challenge of understanding and amplifying relevant immunologic events following sipuleucel-T treatment. The role of autologous cellular immunotherapy is new, and it is one that will continue to evolve in its application in the clinic.

Acknowledgments:

Development of this article was supported by Dendreon Corp. Conflict of interest statement: Dr. Fishman has received honoraria from Dendreon corporation, and had been an investigator on the cited study [2, 3] and Dr. Spiess and Dr. Fishman are current investigators on Dendreon-sponsored research trial (NCT01353222; not cited).

References:

  1. Sheikh NA, Petrylak D, Kantoff PW, Dela Rosa C, Stewart FP, Kuan LY, Whitmore JB, Trager JB, Poehlein CH, Frohlich MW, Urdal DL. Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer. Cancer Immunol Immunother. 2012 Aug 3.
  2. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern H, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010 Jul 29;363(5):411-22.
  3. Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, Provost N, Frohlich MW (2009) Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 115:3670–3679.
  4. Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, Verjee SS, Jones LA, Hershberg RM (2006) Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24:3089–3094
  5. Huber ML, Haynes L, Parker C, Iversen P. Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer. J Natl Cancer Inst. 2012 Feb 22;104(4):273-9.
  6. Kantoff PW, Higano C, Small E, et al. Re: Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer. J Natl Canc Inst. 2012;104:1107-9.
  7. Gulley JL, Leitman SF, Dahut W and Schlom J. Re: Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer. J Natl Canc Inst. 2012;104:1106.
  8. Drake CG. Re: Interdisciplinary Critique of Sipuleucel-T as Immunotherapy in Castration-Resistant Prostate Cancer [epub]. J Natl Canc Inst. 2012.

 

Written by:
Philippe E. Spiess, MD, FACS, FRCS(C), Julio Pow-Sang, MD, and Mayer N. Fishman, MD, PhD 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.

H. Lee Moffitt Cancer Center and Research Institute
Department of Genitourinary Oncology
Correspondence:

Sipuleucel-T immune parameters correlate with survival: An analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer - Abstract

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