ARandomized Phase II Study of Concurrent Docetaxel Plus Vaccine Versus VaccineAlone inMetastatic Androgen-Independent Prostate Cancer

Purpose: Docetaxel has activity against androgen-independent prostate cancer and preclinical studieshave shown that taxane-based chemotherapy canenhance antitumor response of vaccines. The primary objective of this study was to determine if concurrent docetaxel (with dexamethasone) hadanyeffectongeneratinganimmuneresponsetothevaccine.Secondaryendpointswerewhether vaccine couldbe given safelywithdocetaxel and the clinicaloutcomeof the treatment regimen. Experimental Design: The vaccination regimen was composed of (a) recombinant vaccinia virus (rV) that expresses the prostate-specific antigen gene (rV-PSA) admixed with (b) rV that expresses the B7.1costimulatory gene (rV-B7.1), and (c) sequential booster vaccinations with recombinant fowlpox virus (rF-) containing the PSAgene (rF-PSA). Patients receivedgranulocyte macrophage colony-stimulating factor with each vaccination. Twenty-eight patients with metastatic androgen-independent prostate cancer were randomized to receive either vaccine and weekly docetaxel or vaccine alone. Patients on the vaccine alone arm were allowed to cross over to receive docetaxel alone at time of disease progression. The ELISPOTassay was used to monitor immune responses for PSA-specificTcells. Results: The median increase in theseT-cell precursors to PSA was 3.33-fold in both arms following 3 months of therapy. In addition, immune responses to other prostate cancer ^ associated tumor antigens were also detected postvaccination. Eleven patients who progressed on vaccine alone crossed over to receive docetaxel at time of progression. Median progressionfree survival on docetaxel was 6.1months after receiving vaccine comparedwith 3.7monthswith the same regimen in a historical control. Conclusion: This is the first clinical trial to show that docetaxel can be administered safely with immunotherapy without inhibiting vaccine specificT-cell responses. Furthermore, patients previously vaccinated with an anticancer vaccine may respond longer to docetaxel compared with a historical control of patients receiving docetaxel alone. Larger prospective clinical studies will be required to validate these findings. Adenocarcinoma of the prostate is the most common noncutaneous malignancy diagnosed in American males and the second leading cause of cancer death. One of six men will develop clinically significant prostate cancer in his lifetime. During 2005, an estimated 232,900 men will be diagnosed with prostate cancer and 30,350 will die from the disease in the United States (1). Overall survival for patients with metastatic androgen-independent prostate cancer has been improved with a docetaxel-based regimen. The clinical benefit shown in these recent studies is an f3-month increase in survival using an every-3-week regimen of docetaxel (2, 3). However, compared with the every-3-week schedule, weekly docetaxel is associated with significantly less grade 3 or 4 hematologic toxicity. Other studies have looked at combining weekly docetaxel with other agents (4, 5). A randomized phase II trial at the National Cancer Institute compared the addition of daily low-dose thalidomide (200 mg) to weekly docetaxel (30 mg/m) versus docetaxel alone (6). Docetaxel was administered for 3 consecutive weeks of a 4-week cycle. Nine of 25 patients (37%) in the docetaxel alone arm and 25 of 50 patients (50%) in the combination arm had a prostate-specific antigen (PSA) decline of at least 50%. In a recent update, the overall survival of the combination arm was 25.9 months versus 14.7 months in the docetaxel alone arm (P = 0.041; ref. 7). www.aacrjournals.org Clin Cancer Res 2006;12(4) February15, 2006 1260 Cancer Therapy: Clinical Authors’Affiliations: Laboratory of Tumor Immunology and Biology, Medical Oncology Clinical Research Unit, Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, and Clinical Center, NIH, Bethesda, Maryland and Therion Biologics Corporation, Cambridge, Massachusetts Received 9/22/05; revised11/23/05; accepted12/9/05. Grant support: Intramural Research Programof theNIH, National Cancer Institute, Center for Cancer Research. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Requests for reprints: Jeffrey Schlom, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, 10 Center Drive, Room 8B09, Bethesda, MD 20892-1750. Phone: 301-496-4343; Fax: 301-496-2756; E-mail: js141c@nih.gov. F2006 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-05-2059 Research. on May 29, 2017. © 2006 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Newer strategies for the treatment of metastatic androgenindependent prostate cancer are currently being evaluated. The development of vaccine strategies designed to break tolerance and generate a sustained immune response against prostate cancer represents a novel therapeutic approach. Preclinical and clinical studies with a range of vaccines have shown that the induction of T-cell responses directed against a self-antigen can lead to antitumor activity in the absence of toxicity. Both carbohydrate and glycoprotein vaccines using ‘‘self’’ antigens have been administered to patients with prostate cancer. Clinical studies have not yet determined which of these antigens would contribute to the most potent vaccine. Globo H hexasaccharide is a carbohydrate vaccine that has elicited antibody responses as well as declines in PSA velocities when administered to prostate cancer patients (8). MUC-1 and prostate-specific membrane antigen have also been used as targets in various prostate cancer clinical studies (9–11). PSA is a potential target for a prostate cancer vaccine owing to its restricted expression on prostate cancer and normal prostatic epithelium. Miller et al. (12) conducted a phase I trial using a PSA DNA vaccine (pVAX/PSA DNA) in patients with hormone refractory prostate cancer, showing induction of T cells to PSA peptides in patients following vaccine. Because the majority of prostate cancer vaccines tested thus far have used ‘‘self’’ antigens, vaccines and vaccine strategies must be developed to enhance the immunogenicity of these targets. An advantage of using recombinant poxvirus when developing cancer vaccines is that recombinant proteins derived from genes inserted and transcribed in viral genomes are more immunogenic than protein in adjuvant (13–15). The use of poxviral vectors to stimulate an immune response to PSA has been evaluated in several clinical trials (16, 17). The Eastern Cooperative Oncology Group reported (18) a randomized phase II study in which 64 patients with increasing PSA following definitive local therapy with no evidence of disease on scans were randomized to receive four vaccinations with recombinant fowlpox vector (rF-) expressing the PSA gene (rF-PSA, designated ‘‘F’’ for fowlpox) alone or in sequence with recombinant vaccinia vector (rV-) expressing PSA (rV-PSA, designated ‘‘V’’; ref. 18). Patients in arm A received monthly vaccination of FFF, arm B with FFFV, and arm C with VFFF. There was a substantial difference in PSA progression-free survival favoring the VFFF arm (arm C), lending further support to the use of vaccinia priming and avipox vector boosting (19– 22). This study has recently been updated with a median followup time of 50 months. The median time to PSA progression is 9.2, 9.1, and 18.2 months for arms A, B, and C, respectively. The median time to clinical progression has still not been reached for any treatment group with 80% of men in arms A and B free of disease progression compared with 90% of men in arm C free of clinical progression (P = 0.73, log-rank test). These results suggest that men with hormone-dependent prostate cancer and an increasing PSA may derive long-term clinical benefit from vaccinations with poxviruses expressing PSA (23). Costimulatory molecules are critical in the generation of potent T-cell responses, especially to weak antigens such as tumor-associated antigens (TAA). The initiation of a potent immune response requires at least two signals for the activation of naive T cells by antigen-presenting cells. The first signal is antigen specific, delivered through the T-cell receptor via the peptide/MHC, and causes the T cell to enter the cell cycle. The second ‘‘costimulatory’’ signal involves the interaction of a costimulatory molecule [such as B7.1 (CD80)] expressed on antigen-presenting cells, with its ligand on the T cell (the ligand for B7.1 is CD28 and CTLA4; refs. 24–26). We have recently reported the results of two phase II prostate cancer clinical trials where we administered rV-PSA mixed with a recombinant vaccinia containing the T-cell costimulatory molecule B7.1 along with booster vaccinations of avipox-PSA. In the first study, 30 patients with localized prostate cancer were randomized in a 2:1 fashion to receive radiation therapy with vaccination or radiation therapy alone (27). There were eight monthly vaccine injections administered to the patients randomized to the combination therapy in this study. Seventeen of 19 patients assigned to the vaccine arm received all eight doses. Thirteen of these 17 patients had enhanced increases in PSA-specific T cells compared with none in the radiation alone group. This study showed that the vaccine could be given safely and that specific T-cell responses were achieved in the majority of patients (27). In the second study, 42 patients with nonmetastatic hormonerefractory prostate cancer were randomized to receive either vaccination or antiandrogen therapy with nilutamide. If, after 6 months of treatment, the patients had no metastasis and their PSA continued to increase, they could then receive a combination of both treatments. Three patients who