Immunotherapy for Prostate Cancer: Walk, Don't Run

Prostate cancer is not traditionally considered an immunologically responsive malignancy like melanoma or renal cell carcinoma, yet the prostate glands of men with cancer are frequently diffusely infiltrated with both CD4 and CD8 T cells, and several factors suggest that adenocarcinoma of the prostate might prove an attractive target for immunotherapy. First among these is the slow-growing nature of the disease, allowing time for immunological intervention to overcome immunosuppressive factors in the tumor microenvironment and to mount a clinically meaningful response. Second, serum PSA level, while not a true surrogate marker, is routinely utilized in clinical decision making, and can serve to guide the development of immunotherapy approaches. Third, both proteomic and microarray analyses of prostate cancer progression have delineated a number of relatively tissue-specific proteins that may serve as tumor/tissue antigens. Finally, abundant preclinical data suggest that an antitumor immune response can be elicited, particularly when active immunotherapy is combined with maneuvers to mitigate tolerance such as immune checkpoint blockade, androgen ablation, or radiotherapy. At least five phase III immunotherapy trials have been initiated in the context of metastatic, castrate-resistant prostate cancer, but none have yet met their predetermined end points (see Note Added in Proof). In this issue of Journal of Clinical Oncology, McNeel et al report a phase I trial that enrolled men with a minimal disease burden, socalled D0 disease, which represents biochemical (PSA) recurrence after definitive local therapy. As has been the case for nearly all vaccine studies in prostate cancer, a minimal adverse effect profile was noted. The selection of patients with minimal disease makes biologic sense; in such patients the tolerogenic effects of the tumor microenvironment are expected to be minimized. However, quantifying clinical benefit in the biochemically recurrent patient population is especially difficult, since vaccine approaches in prostate cancer generally have not resulted in decreases in PSA. Here, decreases in the rate of PSA rise, as quantified by an increased PSA doubling time (PSADT), were noted, but the clinical benefit of such changes has not been established. In conjunction with applicable clinical readouts, immunological correlates are often utilized to guide vaccine development, and McNeel et al demonstrated the development of a T cell immune response to the target antigen (prostatic acid phosphatase [PAP], as detected by enzymelinked immunospot) in a number of patients. Given the relatively small number of patients studied, a correlation between clinical parameters (PSADT) and immunological readouts was not feasible, but the available data support the notion that this DNA vaccine induced detectable responses in early-stage prostate cancer patients. One of the major challenges in the development of immunotherapy has been the establishment of a clear relationship between the induction of antigenspecific T cell responses and clinical outcome, and it is feasible that a larger trial with this agent could provide such data. A second major challenge facing cancer vaccine development is the selection of appropriate target antigens from the broad pallette available, and much of the significance of this trial lies in the applicability of the DNA vaccine approach to facilitate the evaluation of additional prostate-restricted target antigens in a systematic manner. One of the few immunotherapy agents in late-stage development for prostate cancer is Sipuleucel-T (Dendreon Inc, Seattle WA). In this approach, patients undergo plasmapheresis, and a personalized immunotherapy product is produced by culturing a patient’s peripheral blood monocytes with a proprietary protein that couples granulocytemacrophage colony-stimulating factor with a target antigen (PAP). Phase I and phase III trials of Sipuleucel-T have been reported, with encouraging results. Clinical development of this agent is pivotal on a large ( 500 patients) randomized placebo-controlled phase III trial (ImPACT; Immunotherapy Prostate Adenocarcinoma Treatment) which completed accrual in October 2007, and for which additional survival data are expected sometime this year (see Note Added in Proof). In addition, considerable clinical development has focused on a viral vector approach in which PSA itself is targeted using sequential injections with recombinant vaccinia and fowlpox constructs. Here, both constructs have been engineered to include a number of costimulatory molecules in an effort to augment an immune response. This agent, ProstVacVF (Bavarian Nordic, Mountainview CA), has been evaluated both alone and in combination with conventional therapies for prostate cancer in both early stage and later stage disease. A randomized phase II trial comparing ProstVacVF to placebo in men with asymptomatic, metastatic castrate-resistant prostate cancer was recently reported to demonstrate a survival benefit (www.bavarian-nordic.com), and a phase III trial is planned for 2010. So, two small (approximately 120 patients) randomized trials of immunotherapy for metastatic prostate cancer have reported a clinical benefit, but in both cases the comparator arm was a placebo treatment. While a placebo comparator might seem unwarranted given that every 3-week docetaxel chemotherapy is US Food and Drug Administration–approved for metastatic castrate-resistant prostate cancer, it must be appreciated that both of these trials enrolled only asymptomatic men, and controversy exists regarding the optimal timing of chemotherapeutic intervention in metastatic prostate cancer. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 25 SEPTEMBER 1 2009