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

Abstract

PurposeSipuleucel-T, the first FDA-approved autologous cellular immunotherapy for treatment of advanced prostate cancer, is manufactured by activating peripheral blood mononuclear cells, including antigen presenting cells (APCs), with a fusion protein containing prostatic acid phosphatase. Analysis of data from three phase 3 trials was performed to immunologically characterize this therapy during the course of the three doses, and to relate the immunological responses to overall survival (OS).MethodsSipuleucel-T product characteristics [APC numbers, APC activation (CD54 upregulation), and total nucleated cell (TNC) numbers] were assessed in three randomized, controlled phase 3 studies (N = 737). Antigen-specific cellular and humoral responses were assessed in a subset of subjects. The relationships between these parameters and OS were assessed.ResultsAPC activation occurred in the first dose preparation [6.2-fold, (4.65, 7.70); median (25th, 75th percentile)] and increased in the second [10.6-fold (7.83, 13.65)] and third [10.5-fold (7.89, 13.65)] dose preparations. Cytokines and chemokines associated with activated APCs were produced during the manufacture of each dose; T-cell activation-associated cytokines were detected in the second and third dose preparations. Antigen-specific T cells were detectable after administration of the first sipuleucel-T dose. Cumulative APC activation, APC number, and TNC number correlated with OS (P < 0.05). Antigen-specific immune responses were observed in 78.8 % of monitored subjects and their presence correlated with OS (P = 0.003).ConclusionSipuleucel-T broadly engages the immune system by activating APCs ex vivo and inducing long-lived immune responses in vivo. These data indicate antigen-specific immune activation as a mechanism by which sipuleucel-T prolongs OS.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-012-1317-2) contains supplementary material, which is available to authorized users.

Humoral response to a viral glycan correlates with survival on PROSTVAC-VF

“…For example, the ability to identify nonresponders within the first 3 mo of treatment could enable clinicians to adjust treatments rationally many months to years before clinical assessments (e.g., tumor burden, PSA levels) become reliable indicators of an effective response. Although previous investigations of immune responses to vaccination have found potential associations with clinical responses (1,5,6,10,11), no clinically validated biomarker of efficacy is available for any cancer vaccine. Detailed investigations of T-cell responses, humoral responses to protein antigens, and immunosuppressive T-regulatory cells have not accounted consistently for variation in survival benefit among patients (2,3,5,6).…”

“…Moreover, studies aimed at identifying new biomarkers often lack controls necessary to assess whether a particular candidate biomarker is vaccine specific or is an epiphenomenon arising from nonspecific effects of disease progression (9). Although several promising studies have linked postvaccination immune responses with favorable clinical responses (1,5,6,10,11), none to date has led to a validated companion diagnostic. Therefore new clinically relevant biomarkers of vaccine efficacy are urgently needed.…”

Evaluating immune responses after sipuleucel-T therapy

“…Additionally, 39.5% (60/152) of sipuleucel-T treated patients showed a response to PAP, vs. 5.7% (4/70) of control patients. 4 The humoral response was still detectable 6 months after treatment, with anti PA2024 and anti PAP IgG antibodies continuing to increase after 26 weeks. Sipuleucel-T treated patients who developed at least one peripheral immune Keywords: GU malignancies, immune response, prostate cancer, urology, sipuleucel-T response (T-cell proliferation, IFNg ELI-SPOT or antibody production) to PA2024 or PAP were also associated with significantly better OS (HR D 0.47) (95% CI: 0.29-0.78; P D 0.003).…”

“…Sipuleucel-T treated patients who developed at least one peripheral immune Keywords: GU malignancies, immune response, prostate cancer, urology, sipuleucel-T response (T-cell proliferation, IFNg ELI-SPOT or antibody production) to PA2024 or PAP were also associated with significantly better OS (HR D 0.47) (95% CI: 0.29-0.78; P D 0.003). 4 To understand the effect of sipuleucel-T not just peripherally, but on the tumor microenvironment, Fong et al conducted a phase II clinical trial of sipuleucel-T in the neoadjuvant setting for 37 patients with localized prostate cancer, who were eligible for radical prostatectomy. 5 In this study, they found that prostatectomy specimens of patients treated with sipuleucel-T showed more than a 3 fold increase in infiltrating CD3C, CD4CFOXP3-and CD8C T cells, compared with pretreatment biopsies.…”

Trial Watch: Therapeutic vaccines in metastatic renal cell carcinoma

“…A survival benefit can be observed in the absence of an objective response, as demonstrated by the efficacy of sipuleucel-T in prostate cancer. 88 Moreover, the immune checkpoint inhibitor, ipilimumab, showed distinct radiological response patterns in metastatic melanoma (long stabilization, pre-response flare-up, and delayed response). An early response might not always be a good surrogate for survival.…”