HUMORAL IMMUNE RESPONSE AGAINST NON-TARGETED TUMOR ANTIGENS AFTER TREATMENT WITH SIPULEUCEL-T AND ITS ASSOCIATION WITH IMPROVED CLINICAL OUTCOME.

Publication Type:

Journal Article

Source:

Clinical cancer research : an official journal of the American Association for Cancer Research (2015)

Abstract:

Purpose: Anti-tumor activity of cancer immunotherapies may elicit immune responses to non-targeted (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 (primary antigen). Experimental Design: Serum samples from mCRPC patients enrolled in the placebo-controlled phase 3 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 2 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 post-treatment) 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 mCRPC patients. 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.