The approval of sipuleucel-T, an autologous PAP (prostatic acid phosphatase) directed cell-based immunotherapy manufactured using patients’ own antigen-presenting cells, represented a landmark in the treatment of metastatic cancers because it was the first therapeutic vaccine to show a survival advantage in any tumor type [10
]. In the pivotal 512-patient phase 3 study leading to FDA-approval, men with minimally/asymptomatic metastatic CRPC who received sipuleucel-T demonstrated superior survival than patients receiving placebo (25.8 versus 21.7 months; hazard ratio 0.78; P
= 0.03), but there was no difference in other measurable endpoints such as prostate-specific antigen (PSA) responses or radiographic tumor responses [3
]. Whereas docetaxel was the only other life-prolonging therapy for men with CRPC at the time of its approval, sipuleucel-T now competes with four additional treatment modalities that have all been shown to improve survival: cabazitaxel, abiraterone, radium-223, and MDV3100. This change in the therapeutic landscape, together with an increased awareness that immunotherapy will likely prove most effective in a minimal-disease setting [11
] and/or when combined with other standard therapies [12
], has motivated the design of several clinical trials evaluating sipuleucel-T in novel contexts ().
Selected ongoing prostate cancer immunotherapy trials
The earliest setting in which prostate cancer immunotherapy could be tested is prior to primary therapy (surgery or radiation) for localized disease. To this end, sipuleucel-T has been evaluated in the neoadjuvant space in a phase 2 study enrolling 40 men who are scheduled to undergo subsequent radical prostatectomy (NCT00715104). In this study, individuals were treated with three infusions of sipuleucel-T before radical prostatectomy, with the primary endpoint being analysis of antitumor immune responses in resected prostate glands compared with that in core biopsy specimens collected prior to sipuleucel-T administration. In addition, the potential for augmentation of antitumor immune responses by combining immunotherapy with androgen deprivation therapy in the presurgical setting is an attractive concept. Indeed, key neoadjuvant studies support this combinatorial approach, showing that (even when used alone) androgen ablation induces dense immunological infiltrates into the prostate gland [13
The next setting in which an immunotherapy could be investigated is the biochemical-recurrence state, characterized by PSA elevation after primary prostate cancer therapy [15
]. This disease state represents an ideal setting for immune-based approaches because disease burden is at a minimum and tumor-induced tolerance is expected to be low. Because such patients are often treated with androgen deprivation therapy (although this does not result in any cures), one attractive approach is to combine androgen ablation (given for a defined period of time) with immunotherapy in an effort to eradicate residual prostate cancer cells (or maintain them in a dormant state) in the absence of continued androgen ablation [9
]. Ample preclinical data support this notion, demonstrating that androgen deprivation can potentiate antitumor immunity and augment vaccine efficacy [8
]. However, the optimal sequencing of androgen ablation with immunotherapy is not yet clear (i.e., whether immunotherapy should be delivered before androgen ablation, as a priming maneuver; or after androgen ablation, as an immunological boost). To answer this question clinically, a 60-patient randomized phase 2 trial has been initiated (NCT01431391) in which a standard three-dose course of sipuleucel-T is being administered either 6 weeks before or 12 weeks after a 12-month course of androgen deprivation therapy in men with biochemically recurrent prostate cancer at high risk of metastatic progression. The primary objective of this study is to evaluate PAP-specific effector T-cell and B-cell responses, in an attempt to establish which sequence results in the more robust antitumor immune response. This study will also compare PSA progression and metastasis-free survival in the two treatment arms [17
With the advent of novel hormonal therapies, such as abiraterone and MDV3100, another intriguing concept would be the combination of these agents with immunotherapy approaches. However, the optimal timing of these newer androgen-directed therapies with sipuleucel-T remains unknown. Aiming to shed light on this issue, a 60-patient randomized phase 2 study has been recently launched (NCT01487863); this trial will allocate men with metastatic CRPC to receive 6 months of abiraterone beginning concurrently with the first dose of sipuleucel-T, or 6 weeks after the last dose of sipuleucel-T. As mentioned above, this study’s primary objective is to compare the peripheral immune response between the two treatment arms, although it is certainly conceivable that larger trials employing clinical endpoints could follow. One potential caveat with this trial is that abiraterone treatment requires the concurrent administration of prednisone (10 mg daily), and the effects of corticosteroids on sipuleucel-T efficacy are unknown. In summary, the ongoing trials discussed above will help clarify both the potential utility of sipuleucel-T in early-stage disease as well as its optimal combination with conventional and novel hormonal therapies, although confirmatory trials with placebo-control groups and clinical endpoints will be required for label-expansion purposes.