Prostate Cancer as a Prototype for Vaccine Therapy
Although the vast majority of previous and ongoing vaccine trials have been conducted in patients with metastatic melanoma, several characteristics render prostate cancer a prototype disease for the evaluation of therapeutic cancer vaccines. First, time is often required to generate a sufficient immune response to curtail tumor growth, and prostate cancer is generally an indolent disease that may not lead to metastatic disease or death for over a decade or more. Second, prostate cancer cells express a variety of well-characterized TAAs. Third, the serum marker PSA can be used to identify patients with minimal tumor burden and those responding to therapy. Last, a well-defined nomogram, the Halabi nomogram, can be used at presentation of metastatic disease to predict a patient's probable response to standard of care chemotherapy and/or hormone therapy.
After early clinical trials of the Sipuleucel-T vaccine demonstrated its safety, larger trials were conducted in patients with minimally symptomatic mCRPC. Although a pair of small phase III trials failed to meet their primary endpoint of improved disease progression, there was evidence that Sipuleucel-T prolonged survival in mCRPC. A larger phase III trial was then conducted in which more than 500 patients were enrolled and overall survival (OS) was set as the primary endpoint. In this trial, again, no change in time to cancer progression was seen; however, OS was improved in the vaccine arm (25.8 vs 21.7 months; P = .032; Figure 1, A). In April 2010, the FDA approved Sipuleucel-T for the treatment of minimal or non-symptomatic mCRPC.
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Figure 1.
Overall survival (OS) in patients with metastatic castrate-resistant prostate cancer using cancer vaccines. A) Results of the primary efficacy analysis of treatment with Spiluleucel-T as compared with placebo control. Sipuleucel-T did improve patients' OS (hazard ratio for death = 0.78; 95% confidence interval = 0.61 to 0.98; P = .03) [adapted with permission from reference (41)]. The placebo control consisted of cultured antigen-presenting cells (APCs) from leukapheresis, without prostatic acid phosphatase–granulocyte macrophage colony-stimulating factor (PAP–GM-CSF) antigen. Per the trial protocol, the control group could receive cryopreserved APCs with antigen upon disease progression. B) OS of a randomized, placebo-controlled 43-center trial of PROSTVAC vaccine consisting of recombinant vaccinia and fowlpox vectors containing transgenes for prostate-specific antigen, B7.1, intercellular adhesion molecule 1, and lymphocyte function-associated antigen-3 (PSA-TRICOM) in patients with metastatic castrate-resistant prostate cancer; the trial compared PROSTVAC vaccine vs empty vector. There was an OS advantage of 8.5 months (OS = 25.1 vs 16.6 months; P = .006) and a 44% reduction in death in the vaccine arm [adapted with permission from reference (24)].
A second prostate cancer vaccine has also been evaluated in the same population of men with mCRPC. This "off-the-shelf" platform (PROSTVAC) consists of a recombinant vaccinia virus priming vaccination and multiple fowlpox booster vaccinations. Each vector contains transgenes for PSA and three costimulatory molecules (CD80, intercellular adhesion molecule 1, and lymphocyte function–associated antigen-3 that are collectively designated TRICOM). A 43-center randomized placebo-controlled phase II trial enrolled 125 minimally symptomatic mCRPC patients. Similar to the experience with Sipuleucel-T, treatment with PROSTVAC did not alter time to progression; however, it improved median OS relative to a placebo, the control vector (OS = 25.1 vs 16.6 months, P = .006; Figure 1, B). Over the course of follow-up, 44% fewer patients who received PROSTVAC died compared with the control cohort (hazard ratio [HR] = 0.56). The median OS in a second PROSTVAC single-arm phase II study was 26.6 months, which was similar to that observed in the PROSTVAC arm of the larger PROSTVAC randomized trial.
Another point to consider in the treatment of mCRPC and other cancers is the patients' quality of life. The Sipleucel-T and PROSTVAC vaccines compared favorably with the chemotherapeutic agents and hormonal therapies that are FDA approved for mCRPC, especially because there were fewer serious adverse events seen with these vaccines than with the other agents (Table 3).