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Originally published as JCO Early Release 10.1200/JCO.2009.22.2299 on July 27 2009 © 2009 American Society of Clinical Oncology.
Immunotherapy for Prostate Cancer: Walk, Don't RunJohns Hopkins University Kimmel Cancer Center, Baltimore, MD 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 factors1 in the tumor microenvironment and to mount a clinically meaningful response. Second, serum PSA level, while not a true surrogate marker,2 is routinely utilized in clinical decision making, and can serve to guide the development of immunotherapy approaches. Third, both proteomic3 and microarray analyses4 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 (Note Added in Proof). In this issue of Journal of Clinical Oncology, McNeel et al5 report a phase I trial that enrolled men with a minimal disease burden, so-called 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 enzyme-linked 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 antigen-specific 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 granulocyte-macrophage colony-stimulating factor with a target antigen (PAP). Phase I6,7 and phase III8 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 (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.9 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,8 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.10,11 In contrast to the trials mentioned earlier, standard chemotherapy with docetaxel and prednisone was chosen as the comparator arm in two phase III trials of GM-CSF gene-transduced tumor vaccine (GVAX) prostate (Cell Genesys, San Franciso, CA). This agent is a cellular vaccine product comprised of two allogeneic prostate cancer cell lines engineered to secrete GM-CSF.12 Cell-based vaccine therapies like GVAX prostate have the potential to target multiple antigens, and showed a favorable safety profile with some evidence of clinical efficacy in phase II trials.13–15 Two phase III trials of GVAX prostate were initiated, both with overall survival as the primary end point. Vaccine Immunotheraphy with Allogenic Prostate Cancer Cell Lines 1 (VITAL-1), initiated in 2004, compared GVAX prostate with docetaxel and prednisone chemotherapy in men with asymptomatic prostate cancer. VITAL-2, initiated in 2005, compared the combination of GVAX plus docetaxel (minus prednisone) with standard docetaxel and prednisone in a more challenging patient group, men with symptomatic disease. However, in August 2008, a routine safety review of VITAL-2 by the independent data monitoring committee showed an imbalance of deaths, with 47 observed in the docetaxel and prednisone arm, and 67 in the GVAX and docetaxel combination arm. Based on these data, the VITAL-2 trial was immediately halted and eventually terminated. The biologic basis for this imbalance has yet to be determined. Despite this disappointing outcome, no safety concerns were raised for the VITAL-1 trial, which was not permanently discontinued at that time. However, efficacy concerns prompted a futility analysis of the VITAL-1 data set; the trial had completed accrual in July of 2007. In October 2008, VITAL-1 was reported to have less than a 30% chance of meeting an improved survival end point, and that trial was terminated as well (www.cellgenesys.com). How can these trials inform the ongoing development of immunotherapy for prostate cancer? While ample preclinical data suggest an additive effect for chemotherapy properly timed with GVAX,16 the efficacious dose range for chemotherapy in this setting is surprisingly narrow, and additive (or synergistic) effects are critically dependent on the relative timing of chemotherapy with respect to immunotherapy. Given this complexity, it is noteworthy that a phase II trial evaluating the GVAX and docetaxel combination with varying docetaxel dose levels and/or timing was not conducted in the target patient population before moving to phase III. This caution applies to combinations with other immunotherapy agents as well, emphasizing a need for patience and scientific rigor in moving immunologically active combinations forward from preclinical data. The VITAL-1 trial, which compared GVAX to docetaxel, seems to offer a somewhat different lesson, especially when considered alongside the placebo-controlled Sipuleucel T and ProstVac trials outlined earlier. Because docetaxel chemotherapy results in a documented survival benefit in men with castrate-resistant prostate cancer,17,18 it might be somewhat ambitious to expect single-agent immunotherapy to have an impact similar to cytotoxic chemotherapy, particularly in patients with a significant disease burden. Thus, unless a placebo control arm is utilized, chemotherapy administration should be standardized across treatment groups. These two key considerations, phase II evaluation of combination approaches and careful consideration regarding docetaxel chemotherapy, are not limited to GVAX immunotherapy for prostate cancer, and serve to inform the development of other immunotherapeutic agents as well. Advanced prostate cancer is a challenging disease, and phase III prostate cancer trials which fail to demonstrate efficacy or which are prematurely terminated are in no way unique to the field of immunotherapy. Salient recent examples include a more than 900 patient phase III trial of the endothelin-A receptor antagonist Atrasentan (Abbott, Abbott Park, IL) which failed to meet its time to progression end point, as well as a phase III trial combining docetaxel with the vitamin D analog DN-101 (Novacea, San Francisco CA). Like VITAL-2, it was halted before final analysis because of an imbalance of deaths in the experimental arm. Unique considerations in the development of immunotherapy encompass a number of barriers which are predominant in advanced prostate cancer patients, including high circulating levels of immunosuppressive cytokines, such as transforming growth factor-β,19 regulatory T cells,20 and immunological checkpoints mediated by cell surface molecules such as CTLA-4,21 PD-1,22 and others. These formidable barriers to immunotherapy suggest that, instead of ignoring these challenges and injudiciously flinging the latest vaccine or checkpoint inhibitor against a wall of metastatic disease (especially as a single agent), it might make sense to adopt a more considered approach, moving toward studies in patients with a lower disease burden, and carefully exploring combination approaches in a randomized phase II setting before moving forward. Indeed, considerable preclinical data support the concept of combination immunotherapy. In models of advanced disease, vaccines alone are relatively ineffective, whereas combining active immunotherapy with checkpoint antagonists (anti-CTLA-4,23 anti-PD-1,24 anti-LAG-325), or immune agonists such as anti-41BB26, results in a significant treatment effect. The McNeel et al DNA vaccine trial reported in this issue represents a rational approach to a number of the challenges facing the development of prostate cancer immunotherapy, providing a model for testing various target antigens and combinations in early-stage disease before proceeding with efforts to establish clinical benefit through large randomized trials later in the disease process. Note Added in Proof On April 28, 2009, data from a randomized phase III trial of sipuleucet-T were presented at a meeting of the American Urological Association. The results showed that the study met its primary end point, a 22% reduction in the risk of death as compared to placebo. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Charles G. Drake, Medarex Inc (C), BMS (C), Dendreon, Inc (C) Stock Ownership: Charles G. Drake, Amplimmune Honoraria: None Research Funding: Charles G. Drake, Cell Genesys, Inc Expert Testimony: None Other Remuneration: Charles G. Drake, Medarex, Inc REFERENCES 1. Drake CG, Jaffee E, Pardoll DM: Mechanisms of immune evasion by tumors. Adv Immunol 90:51–81, 2006.[Medline] 2. Collette L, Burzykowski T, Schroder FH: Prostate-specific antigen (PSA) alone is not an appropriate surrogate marker of long-term therapeutic benefit in prostate cancer trials. Eur J Cancer 42:1344–1350, 2006.[CrossRef][Medline] 3. Taylor BS, Varambally S, Chinnaiyan AM: Differential proteomic alterations between localised and metastatic prostate cancer. Br J Cancer 95:425–430, 2006.[CrossRef][Medline] 4. Rhodes DR, Barrette TR, Rubin MA, et al: Meta-analysis of microarrays: Interstudy validation of gene expression profiles reveals pathway dysregulation in prostate cancer. Cancer Res 62:4427–4433, 2002. 5. McNeel DG, Dunphy EJ, Davies JG, et al: Safety and immunological efficacy of a DNA vaccine encoding prostatic acid phosphatase in patients with stage D0 prostate cancer. J Clin Oncol 27:4047–4054, 2009. 6. Burch PA, Breen JK, Buckner JC, et al: Priming tissue-specific cellular immunity in a phase I trial of autologous dendritic cells for prostate cancer. Clin Cancer Res 6:2175–2182, 2000. 7. Small EJ, Fratesi P, Reese DM, et al: Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. J Clin Oncol 18:3894–3903, 2000. 8. Small EJ, Schellhammer PF, Higano CS, et al: Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24:3089–3094, 2006. 9. Arlen PM, Gulley JL, Madan RA, et al: Preclinical and clinical studies of recombinant poxvirus vaccines for carcinoma therapy. Crit Rev Immunol 27:451–462, 2007.[Medline] 10. Schurko B, Oh WK: Docetaxel chemotherapy remains the standard of care in castration-resistant prostate cancer. Nat Clin Pract Oncol 5:506–507, 2008.[CrossRef][Medline] 11. Berthold DR, Pond GR, Soban F, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: Updated survival in the TAX 327 study. J Clin Oncol 26:242–245, 2008. 12. 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Miller AM, Lundberg K, Ozenci V, et al: CD4+CD25high T cells are enriched in the tumor and peripheral blood of prostate cancer patients. J Immunol 177:7398–7405, 2006. 21. Fong L, Kwek SS, O'Brien S, et al: Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF. Cancer Res 69:609–615, 2009. 22. Chen L: Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol 4:336–347, 2004.[CrossRef][Medline] 23. Hurwitz AA, Foster BA, Kwon ED, et al: Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade. Cancer Res 60:2444–2448, 2000. 24. Hirano F, Kaneko K, Tamura H, et al: Blockade of B7–H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 65:1089–1096, 2005. 25. Grosso JF, Kelleher CC, Harris TJ, et al: LAG-3 regulates CD8 T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest 117:3383–3392, 2007.[CrossRef][Medline] 26. Wilcox RA, Flies DB, Zhu G, et al: Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors. J Clin Invest 109:651–659, 2002.[CrossRef][Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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