On the basis of a series of phase III trials, including a pivotal 512-patient study [1
], sipuleucel-T was approved in 2010 for the treatment of metastatic, castration-resistant prostate cancer (mCRPC) [1
]. Results from that trial showed a statistically significant survival advantage, with men in the active treatment group surviving 25.8 months, as opposed to 21.7 months in the placebo group [hazard ratio (HR) =0.78, P
=0.03]. This result marked the first time that treatment with a cancer ‘vaccine’ resulted in a survival benefit in a metastatic solid tumor, and was, thus, critically important for cancer immunotherapy. Sipuleucel-T (Dendreon, Seattle, WA, USA) is a personalized, cell-based immunotherapy manufactured using patients’ own leukocytes, and is grossly similar to other dendritic cell vaccine approaches [2
]. To generate a dose of sipuleucel-T, patients undergo a leukapheresis procedure, and the resulting cells are transferred to one of several processing facilities wherein final product is prepared by incubating enriched monocytes with a proprietary construct that fuses prostatic acid phosphatase (PAP) with granulocyte macrophage colony stimulating factor (GM-CSF). Here, GM-CSF serves to activate and mature the dendritic cells that initiate an immune response, and potentially to direct the PAP protein into these cells [3
]. When sipuleucel-T was approved in 2010, men with mCRPC had only a handful of available treatment options. In the timeframe following approval, several additional agents have become available for men with mCRPC; these include the novel hormonal therapy abiraterone acetate (Zytiga, Janssen) [4
], as well as the novel taxane cabazitaxel (Jevtana, Sanofi Aventis) [5
], both of which demonstrated a survival benefit in men with mCRPC who had progressed on docetaxel chemotherapy. This change in the clinical landscape, as well as increasing awareness that immunotherapy will most likely prove maximally beneficial in the setting of a minimal disease burden [6
] have motivated the initiation of a series of clinical trials aimed at testing the efficacy and feasibility of administering sipuleucel-T in earlier stages of prostate cancer.
Perhaps the earliest stage at which immunotherapy could be used would be prior to primary prostatectomy (). In this regard, sipuleucel-T was recently administered to approximately 40 men prior to surgery in a multisite phase II trial. This study, (NCT00715104), has completed enrollment; the primary endpoint involves immunological analysis of the prostatectomy specimens. Results are pending at the time of this review. In addition, after primary surgery or radiation therapy, approximately 30–40% of men with prostate cancer present with a rising prostate-specific antigen (PSA) without evidence of overt metastatic disease [7
]. This disease state, known as biochemical recurrence, represents a nearly ideal setting for immunological intervention, as the cancer has clearly recurred but disease burden is at a minimum. Men with biochemically recurrent prostate cancer are commonly treated with hormonal therapy (pharmacological castration), although data that early intervention with androgen ablation results in a significant clinical benefit are somewhat scant [8
]. Thus, one combinatorial approach might be to combine androgen ablation with immunotherapy in an effort to modulate PSA kinetics (ultimately, slowing the onset of metastases), or to perhaps initiate an antitumor immune response that could maintain PSA at steady state in the absence of continuing androgen ablation [9
]. Preclinical data support this notion, showing that androgen ablation can augment vaccine efficacy [10
]. Clinical trial data support this combination as well, including key neoadjuvant studies showing that androgen ablation results in an immunological infiltrate into the prostate gland [12
]. However, it is not yet clear whether immunotherapy should be administered before androgen ablation (as a ‘priming’ maneuver), or after (serving as an immunological boost). To explore this sequencing issue clinically, a randomized phase II trial has been initiated. In this study (NCT01431391), a standard three-dose course of sipuleucel-T will be administered either 2 weeks before, or 12 weeks into a 12-month course of standard androgen ablation therapy. The primary endpoints of this 60-patient randomized trial will be immune activation related, in an attempt to determine which sequence results in the more robust anti-PAP immune response.
Selected prostate cancer immunotherapy agents and trials
Another key clinical question involves the novel hormonal therapy, abiraterone acetate, which is currently FDA approved for men who have progressed on chemotherapy. A prechemotherapy trial of abiraterone acetate has also been completed, an important clinical question is whether sipuleucel-T should be administered before abiraterone acetate, or concurrently with that agent. To that end, a phase II combination trial has recently been announced. This trial (NCT01487863) will randomize 60 men with asymptomatic or minimally symptomatic metastatic CRPC to receive a standard course of sipuleucel-T followed by abiraterone acetate, or to a regimen in which both treatments are initiated concurrently. Similar to the study in biochemically recurrent disease discussed above, the primary endpoints of this trial will be immunological, but it is certainly conceivable that larger trials with clinical endpoints could follow. One issue in this trial is that abiraterone acetate is generally administered together with continuous prednisone (5 mg twice daily), and the effects of corticosteroid treatment on sipuleucel-T efficacy are currently unknown. Taken together, this series of trials will help to clarify a potential role for sipuleucel-T earlier in the disease course, but larger confirmatory trials with clinical endpoints will likely be required for label expansion purposes.