Abstract 2542: Sipuleucel-T-induced immune response against secondary cancer antigens is associated with improved overall survival
Authors: GuhaThakurta Debraj , Fan Li-Qun , Vu Tuyen , Stewart Francis , Kantoff Philip , Small Eric , Higano Celeste , Gardner Thomas , Sheikh Nadeem , Trager James 
Published: May 2015

Abstract
Introduction and Objective: Tumor cell death in response to immunotherapy may lead to the release of secondary (non-targeted) cancer antigens that prime subsequent immune responses (antigen spread) 1. This may contribute to tumor control and reveal post-treatment biomarkers of clinical outcome. Sipuleucel-T, an immunotherapy targeted towards the prostate-specific antigen, prostatic acid phosphatase, is approved in the US and EU for treatment of asymptomatic or minimally symptomatic, metastatic castration-resistant prostate cancer. We evaluated: (i) antigen spread after sipuleucel-T treatment, based on IgG antibody responses against secondary cancer antigens, and (ii) association of such IgG responses with overall survival (OS).
Methods: ProtoArray®, an unbiased protein microarray platform, was used to characterize the spectrum of serum IgG responses after treatment. IgG responses against secondary antigens were confirmed using an independent platform, Luminex®, xMAP®. Pre- and post- treatment sera from two clinical trials of sipuleucel-T were analyzed: IMPACT 2 (double-blind, placebo-controlled, phase 3, NCT00065442) and ProACT (open-label, phase 2, NCT00715078). The correlations between IgG responses (≥ 2 fold elevation post-treatment) and OS were assessed in IMPACT using a Cox regression model, adjusted for baseline PSA, LDH, bone lesions, Gleason score, and prior bisphosphonate use.
Results: Serum IgG responses (p&lt;10-3) towards several secondary cancer antigens (PSA, hK2/KLK2, K-Ras, E-Ras, and LGALS8/PCTA-1) were observed after treatment with sipuleucel-T in IMPACT as well as ProACT. Across trials, the frequency of patients with IgG responses after sipuleucel-T treatment was: ≥25% for PSA, ≥33% for hK2, ≥36% for K-Ras, ≥39% for E-Ras, ≥24% for LGALS8. These IgG responses were observed as early as 2 weeks and up to 6 months after treatment with sipuleucel-T. Control arm patients in IMPACT did not show such responses (p&gt;0.01). In the sipuleucel-T arm of IMPACT (N=140), an IgG response to PSA ≈2 weeks after treatment was positively correlated with increased OS, compared to patients with no IgG response to PSA (Cox p&lt;0.01, HR≈0.41 [95% CI=0.22-0.78]). Other IgG responses (such as those against E-Ras and hK2) at ≈2 or ≈10 weeks after treatment, also showed trends towards improved OS.
Conclusions: Sipuleucel-T elicited IgG responses against multiple cancer antigens. Sipuleucel-T- induced IgG response against PSA was positively correlated with improved OS. These data enhance our understanding of sipuleucel-T's mechanism of action, and may help to identify pharmacodynamic biomarkers of clinical outcome. The methods and results presented here may also help in the characterization of antigen spread and pharmacodynamic biomarkers after treatment with other cancer immunotherapies.
1. Ribas A, et al. Trends Immunol. 24:58-61 (2003)
2. Kantoff PW, et al. N Engl J Med. 363:411-22 (2010)
Citation Format: Debraj GuhaThakurta, Li-Qun Fan, Tuyen Vu, Francis Stewart, Philip Kantoff, Eric Small, Celeste Higano, Thomas Gardner, Nadeem Sheikh, James Trager. Sipuleucel-T-induced immune response against secondary cancer antigens is associated with improved overall survival. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2542. doi:10.1158/1538-7445.AM2014-2542