Sequencing of Sipuleucel-T and Androgen Deprivation Therapy in Men with Hormone-Sensitive Biochemically Recurrent Prostate Cancer: A Phase II Randomized Trial

Abstract

Purpose: STAND, a randomized, phase II, open-label trial (NCT01431391), assessed sequencing of sipuleucel-T (an autologous cellular immunotherapy) with androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC) patients at high risk for metastasis.Experimental Design: Men with BRPC following prostatectomy and/or radiotherapy, a PSA doubling time 12 months, and no metastasis were enrolled. Patients were randomized (34/arm) to sipuleucel-T followed by ADT (started 2 weeks after sipuleucel-T completion), or ADT followed by sipuleucel-T (started 12 weeks after ADT initiation); ADT continued for 12 months in both arms. The primary endpoint was PA2024-specific T-cell response [enzyme-linked immunospot (ELISPOT)] over time.Results: PA2024-specific ELISPOT responses over time were similar between groups, except at week 6, where responses were higher with sipuleucel-T!ADT versus ADT!sipuleucel-T (P ¼ 0.013). PA2024-specific T-cell proliferation responses, averaged across time points, were approximately 2-fold higher with sipuleucel-T!ADT versus ADT!sipuleucel-T (P ¼ 0.001). PA2024-specific cellular and humoral responses and prostatic acid phosphatase-specific humoral responses increased significantly versus baseline (P < 0.001) and were maintained for 24 months (both arms). Median time-to-PSA recurrence was similar between arms (21.8 vs. 22.6 months, P ¼ 0.357). Development of a PA2024-specific humoral response correlated with prolonged time-to-PSA progression (HR, 0.22; 95% CI, 0.08-0.67; P ¼ 0.007). Sipuleucel-T with ADT was generally well tolerated.Conclusions: Sipuleucel-T!ADT appears to induce greater antitumor immune responses than the reverse sequence. These results warrant further investigation to determine whether this sequence leads to improved clinical outcomes, as well as the independent contribution of ADT alone in terms of immune activation.

Phase I clinical trial of sipuleucel-T combined with escalating doses of ipilimumab in progressive metastatic castrate-resistant prostate cancer

“…Studies of the pattern of rise in immunoglobulin levels after SIP-T show a maximal increase 2 weeks after the third infusion of SIP-T, which was continuously maintained without any further augmentation 9. A similar pattern of maximal immunoglobulin rise soon after the third dose of SIP-T without any further subsequent increase was also observed in the STAND trial 10. This pattern of maximal immunoglobulin increase after three cycles of SIP-T has been consistent in all the reported trials.…”

Androgen deprivation and immunotherapy for the treatment of prostate cancer

“…T-cell responses were assessed by IFNγ ELISPOT and were similar between the groups at all time points except week 6, where there was significantly higher IFNγ production in sip-T→ADT compared to ADT→sip-T (p=0.013). Furthermore, T cell proliferation was 2-fold higher in sip-T→ADT compared to ADT→sip-T (Antonarakis et al 2016b). The authors concluded that the timing of androgen deprivation therapy might affect the efficacy of immunotherapy, and that a preferred sequence would be to use sip-T prior to ADT in this patient population.…”

“…Antigen-specific T cell proliferation and IFNγ secretion was significantly higher in patients treated with sip-T compared to control patients (Kantoff et al 2010; Sheikh, et al 2013). While sip-T was approved for patients already receiving ADT, there have been two studies examining the administration of timing of ADT with sip-T. One study compared the administration of the LHRH agonist leuprolide before sip-T (ADT→sip-T) or after sip-T (sip-T→ADT) in patients with non-castrate, PSA-recurrent prostate cancer (Antonarakis, et al 2016b). PA2024-specific humoral responses were significantly elevated following sip-T treatment, although there was no difference between the two arms.…”

“…Animal studies also suggested that androgen deprivation reduced tolerance to prostate-expressed antigens, further suggesting that it might best be employed prior to immunotherapy (Drake et al 2005). However, experimental evidence from other human trials has suggested that anti-tumor vaccination may best be employed prior to androgen deprivation, using androgen deprivation to modulate the response to vaccination, rather than the reverse (Antonarakis, et al 2017; Madan et al 2008). The mechanism for this is not entirely understood, but may be related to changes that occur with persistent androgen deprivation.…”

New Combination Strategies Using Programmed Cell Death 1/Programmed Cell Death Ligand 1 Checkpoint Inhibitors as a Backbone

“…The first and only approved DC vaccine is Sipuleucel-T, which targets prostatic acid phosphatase and has been shown to improve OS in patients with metastatic CRPC but showed no impact on PFS or PSA levels [58]. Sipuleucel-T combined with the androgen receptor inhibitor enzalutamide concurrently or sequentially has been investigated in patients with CRPC and results in objective radiological and PSA tumor marker responses [59]. Combination of peptide-antigen loaded DCs or intratumoral injection of immature DCs with checkpoint inhibitors have been studied and efficacy was noted in preclinical mouse models [60–63].…”