Humoral immune response against nontargeted tumor antigens after treatment with sipuleucel-T and its association with improved clinical outcome

Debraj Guha Thakurta, Nadeem A. Sheikh, Li Qun Fan, Harini Kandadi, T. Craig Meagher, Simon J. Hall, Philip W. Kantoff, Celestia S. Higano, Eric J. Small, Thomas A. Gardner, Kate Bailey, Tuyen Vu, Todd Devries, James B. Whitmore, Mark W. Frohlich, James B. Trager, Charles G. Drake

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

Purpose: Antitumor activity of cancer immunotherapies may elicit immune responses to nontargeted (secondary) tumor antigens, or antigen spread. We evaluated humoral antigen spread after treatment with sipuleucel-T, an immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC), designed to target prostatic acid phosphatase (PAP; primary antigen). Experimental Design: Serum samples from patients with mCRPC enrolled in the placebo-controlled phase III IMPACT study (evaluable n = 142) were used to assess humoral antigen spread after treatment with sipuleucel-T. Immunoglobulin G (IgG) responses to self-antigens (including tumor antigens) were surveyed using protein microarrays and confirmed using Luminex xMAP. IgG responses were subsequently validated in ProACT (n= 33), an independent phase II study of sipuleucel-T. Association of IgG responses with overall survival (OS) was assessed using multivariate Cox models adjusted for baseline prostate-specific antigen (PSA) and lactate dehydrogenase levels. Results: In patients from IMPACT and ProACT, levels of IgG against multiple secondary antigens, including PSA, KLK2/hK2, K-Ras, E-Ras, LGALS8/PCTA-1/galectin-8, and LGALS3/galectin-3, were elevated after treatment with sipuleucel-T (P < 0.01), but not control. IgG responses (≥2-fold elevation posttreatment) occurred in ≥25% of patients, appeared by 2 weeks after sipuleucel-T treatment, and persisted for up to 6 months. IgG responses to PSA and LGALS3 were associated with improved OS in sipuleucel-T-treated patients from IMPACT (P < 0.05). Conclusions: Sipuleucel-T induced humoral antigen spread in patients with mCRPC. IgG responses were associated with improved OS in IMPACT. The methods and results reported may identify pharmacodynamic biomarkers of clinical outcome after sipuleucel-T treatment, and help in clinical assessments of other cancer immunotherapies.

Original languageEnglish (US)
Pages (from-to)3619-3630
Number of pages12
JournalClinical Cancer Research
Volume21
Issue number16
DOIs
StatePublished - Aug 15 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Thakurta, D. G., Sheikh, N. A., Fan, L. Q., Kandadi, H., Meagher, T. C., Hall, S. J., Kantoff, P. W., Higano, C. S., Small, E. J., Gardner, T. A., Bailey, K., Vu, T., Devries, T., Whitmore, J. B., Frohlich, M. W., Trager, J. B., & Drake, C. G. (2015). Humoral immune response against nontargeted tumor antigens after treatment with sipuleucel-T and its association with improved clinical outcome. Clinical Cancer Research, 21(16), 3619-3630. https://doi.org/10.1158/1078-0432.CCR-14-2334