Prostate Cancer Vaccine Research Articles

Orange Alert for Oncologists

Coping with terrorism and its consequences has become a part of our daily life, particularly for those of us with family or friends affected by 9/11, for those in the military, and for those of us who travel a lot, but it has only rarely affected our work as physicians and clinical researchers. The assassination of physicians in abortion clinics was perhaps our first close encounter with fundamentalist ideologues. Recently, the same misguided violence has been directed at members of our subspecialty who have chosen the threat of violenceastheirmeansofprotestovertheprofessionalnegative opinions about a vaccine for prostate cancer. As recounted in recent stories in the lay press [1], the Provenge (Dendreon Corporation, Seattle, WA) vaccine for treatment of prostate cancer was recommended for marketing approval by a vaccine advisory group, a nononcologic committee, at the U.S. Food and Drug Administration (FDA), despite the vaccine’s failure to achieve a positive responseendpointinitspivotalphaseIIItrial.TheFDAhas not accepted that recommendation, and for good reason. HowardScher,awell-knownandhighlyrespectedpros

TGF-beta insensitive dendritic cells: an efficient vaccine for murine prostate cancer.

Dendritic cells (DCs) are highly potent initiators of the immune response, but DC effector functions are often inhibited by immunosuppressants such as transforming growth factor beta (TGF-beta). The present study was conducted to develop a treatment strategy for prostate cancer using a TGF-beta-insensitive DC vaccine. Tumor lysate-pulsed DCs were rendered TGF-beta insensitive by dominant-negative TGF-beta type II receptor (TbetaRIIDN), leading to the blockade of TGF-beta signals to members of the Smad family, which are the principal cytoplasmic intermediates involved in the transduction of signals from TGF-beta receptors to the nucleus. Expression of TbetaRIIDN did not affect the phenotype of transduced DCs. Phosphorylated Smad-2 was undetectable and expression of surface co-stimulatory molecules (CD80/CD86) were upregulated in TbetaRIIDN DCs after antigen and TGF-beta1 stimulation. Vaccination of C57BL/6 tumor-bearing mice with the TbetaRIIDN DC vaccine induced potent tumor-specific cytotoxic T lymphocyte responses against TRAMP-C2 tumors, increased serum IFN-gamma and IL-12 level, inhibited tumor growth and increased mouse survival. Furthermore, complete tumor regression occurred in two vaccinated mice. These results demonstrate that blocking TGF-beta signals in DC enhances the efficacy of DC-based vaccines.

Dendritic cells program non‐immunogenic prostate‐specific T cell responses beginning at early stages of prostate tumorigenesis

Prostate cancer promotes the development of T cell tolerance towards prostatic antigens, potentially limiting the efficacy of prostate cancer vaccines targeting these antigens. Here, we sought to determine the stage of disease progression when T cell tolerance develops, as well as the role of steady state dendritic cells (DC) and CD4(+)CD25(+) T regulatory cells (Tregs) in programming tolerance. The response of naïve HA-specific CD4(+) T cells were analyzed following adoptive transfer into Pro-HA x TRAMP transgenic mice harboring variably-staged HA-expressing prostate tumors on two genetic backgrounds that display different patterns and kinetics of tumorigenesis. The role of DC and Tregs in programming HA-specific CD4 cell responses were assessed via depletion. HA-specific CD4 cells underwent non-immunogenic responses at all stages of tumorigenesis in both genetic backgrounds. These responses were completely dependent on DC, but not appreciably influenced by Tregs. These results suggest that tolerogenicity is an early and general property of prostate tumors.

Randomized, double-blind, vector-controlled study of targeted immunotherapy in patients (pts) with hormone-refractory prostate cancer (HRPC)

2501 Background: Therapeutic vaccines for prostate cancer have yielded encouraging data in uncontrolled Phase 1 and 2 studies. PROSTVAC-VF comprises 2 recombinant viral vectors each containing genes encoding the prostate-specific antigen (PSA) gene modified to optimize antigen presentation in HLA-A2+ pts and 3 T-cell costimulatory molecules (B7.1, LFA3, and ICAM-1 [TRICOM]). These vectors are administered in a heterologous prime-boost regimen with concurrent low-dose GM-CSF to enhance recruitment of antigen-presenting cells to the immunization site. Here we report results of a Phase 2 study in pts with metastatic HRPC. Methods: In this randomized, double-blind, controlled study, pts were randomized 2:1 to receive either PROSTVAC-VF plus GM-CSF or Control (empty vectors plus GM-CSF placebo) for 24 weeks. Eligible pts had rising PSA despite castrate testosterone levels and measurable, asymptomatic or non-narcotic-dependent metastases (positive bone scan or lymph node metastases on abdominal-pelvic CT scan). The primary endpoint is progression-free survival (PFS), with progression defined as appearance of new lesions on bone scan or RECIST-defined progression of nodal metastases. The planned sample size was 120 pts. The study was designed to detect a difference of 38% vs 12% PFS at Week 24 with a 2-sided α of 0.05 and 80% power. An independent Data Monitoring Committee evaluated safety data quarterly. Results: 125 pts were enrolled. Demographics are available for 122 pts (mean age, 73.3 years [range, 52–94]; ∼11% African American). Common adverse events (AEs) in 106 evaluable pts (blinded as of Jan 2006) included immunization site reactions (73%), fatigue (26%), fever (14%), and nausea (13%). The majority were of Grade 1/2 severity. Serious AEs attributed to immunization included 1 thrombotic thrombocytopenic purpura (TTP) event. Conclusions: A large, randomized, controlled study of therapeutic immunization with PROSTVAC-VF in 125 pts with metastatic HRPC has been completed. The therapy is well tolerated and findings are consistent with Phase 1 results, but also included a single case of TTP. Full efficacy data collection is ongoing. [Table: see text]

A randomized pilot study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen independent prostate cancer

2531 Background: Docetaxel has activity against androgen insensitive prostate cancer (AIPC) and preclinical studies have demonstrated that taxane-based chemotherapy can enhance antitumor response of vaccines. The primary objective of this study was to determine: if concurrent docetaxel (with dexamethasone) had any effect on generating an immune response to a prostate cancer vaccine in patients with metastatic AIPC; secondary endpoints werewhether vaccine could be given safely with docetaxel, and the clinical outcome of the treatment regimen. Methods: The vaccination regimen was composed of (1) recombinant vaccinia virus (rV) that expresses the prostate-specific antigen gene (rV-PSA) admixed with (2) rV that expresses the B7.1 costimulatory gene (rV-B7.1), and (3) sequential booster vaccinations with recombinant fowlpox virus containing the PSA gene (rF-PSA). Patients received GM-CSF with each vaccination. Twenty-eight patients with metastatic AIPC 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. An ELISPOT assay for IFN-gamma production was used to monitor immune responses for PSA-specific T cells. Results: The median increase in these T-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 post-vaccination. Eleven patients who progressed on vaccine alone crossed over to receive docetaxel at time of progression. Median PFS on docetaxel was 6.1 months after receiving vaccine compared to 3.7 months with the same regimen in a historical control. Conclusions: This is the first clinical trial to demonstrate that docetaxel can be administered safely with immunotherapy, and without inhibiting vaccine specific T-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. No significant financial relationships to disclose.

Combination immunotherapy with prostatic acid phosphatase pulsed antigen‐presenting cells (provenge) plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy

APC8015 (sipuleucel-T) is a cellular prostate cancer vaccine containing autologous antigen-presenting cells (APC) loaded with PA2024, a recombinant prostatic acid phosphatase/granulocyte-macrophage-colony-stimulating factor fusion protein, as the immunogen. Bevacizumab is a recombinant antibody against vascular endothelial growth factor, a proangiogenic protein with inhibitory effects on APC. A clinical trial was conducted to determine the prostate-specific antigen (PSA) and immunomodulatory effects of this combination immunotherapy. Patients with androgen-dependent prostate cancer who had received prior definitive therapy with nonmetastatic, recurrent disease as manifested by a rising PSA of between 0.4 ng/mL and 6.0 ng/mL were enrolled. APC8015 was given intravenously(i.v.) on Weeks 0, 2, and 4. Bevacizumab was given at a dose of 10 mg/kg i.v. on Weeks 0, 2, 4, and every 2 weeks thereafter until toxicity or disease progression. PSA changes were recorded and the PSA doubling time (PSADT) was calculated. Immune response versus PA2024 was measured at baseline and after treatment by T-cell proliferation and interferon-gamma enzyme-linked immunospot (ELISPOT) assays. Twenty-two patients were treated. One patient achieved a > or =50% decrease in PSA. Nine patients exhibited some decrease in PSA from baseline, ranging from 6% to 72%, with the PSA of 3 patients decreasing at least 25%. The median pretreatment PSADT for the 20 evaluable patients was 6.9 months and the median posttreatment PSADT was 12.7 months (P = .01). All patients demonstrated induction of an immune response against PA2024. The combination of APC8015 and bevacizumab induces an immune response and modulates PSA in patients with biochemically recurrent prostate cancer.

Therapeutic Vaccines for Prostate Cancer

Prostate cancer is the most common, noncutaneous cancer for men in the U.S., leading to more than 30,000 deaths a year. Vaccines for prostate cancer, which for several years have been shown to generate immunologic responses, are beginning to show significant clinical promise. At present, numerous therapeutic options are being investigated, including autologous and allogeneic whole-tumor cell vaccines, dendritic cell vaccines, and poxvirus-based vaccines. Advances in basic immunology have translated into new, more complex therapeutic strategies. The findings from current trials and the demonstrated potential to combine vaccines with conventional therapies herald a promising future for the treatment of prostate cancer. This review highlights recent advances and clinical trials in immunotherapy for prostate cancer, along with current thoughts on immunologic and clinical monitoring of these trials.

Introduction to the New Section

Although the elements of oncological practice are not mutated when one leaves the academic environment to enter the domain of community oncology, the mindset certainly shifts. In the confines of the cancer center, the emphasis is on conducting a scientifically valid experiment. The patient, who is generally referred specifically for a treatment protocol, must meet all pre-expressed criteria for entry on the protocol—age, stage, performance status, organ function, absence of previous malignancy, etc. The protocol-imposed treatment specifics of scheduling, dosing, and follow-up must perforce be adhered to diligently. We are taught that a clinical trial, whether randomized or otherwise, is good medicine [1], not only for the greater good of advancing knowledge and improving treatment for others, but also for the intended direct benefit to the participating patient, the subject of the experiment. Moreover, anything less is unethical. However, upon entering the community, we frequently find that a clinical trial is not an option: there may be no appropriate trial open locally, and the patient may not wish to travel to the nearest mecca or may not wish to participate in “an experiment.” And not infrequently, data from well-done trials or published guidelines are not applicable to the patient at hand. Then what do you do, doc? To help answer this question, we are launching a new section in The Oncologist, which we perhaps uncreatively will call The Community Oncologist. Because the focus of The Oncologist has always been on the practicing oncologist, it is appropriate for the reader to ask: in what new directions will we be going? First, we will publish solicited reviews of new and developing areas of therapeutics, as exemplified by the accompanying review, “Therapeutic Vaccines in Prostate Cancer” by Tarassoff et. al. [2]. There was a day when the practicing oncologist did not need to know about cancer vaccines, as they were unsuccessful or unproven. Now, vaccines are rapidly scoring victory after victory in treating lymphomas and leukemia, in cervical cancer prevention, and even in treating pancreatic cancer and melanoma. Drs. Tarassoff, Arlen, and Gulley have reviewed the rapid progress in prostate cancer vaccines for us. We will also publish issues facing us daily in practice,

976: Immunotherapy with GVAX® Vaccine for Prostate Cancer Improves Predicted Survival in Metastatic Hormone Refractory Prostate Cancer: Results from Two Phase 2 Studies

You have accessJournal of UrologyModerated Poster, Monday, May 22, 2006, 3:30 - 5:30 pm1 Apr 2006976: Immunotherapy with GVAX® Vaccine for Prostate Cancer Improves Predicted Survival in Metastatic Hormone Refractory Prostate Cancer: Results from Two Phase 2 Studies John M. Corman, Eric Small, David Smith, Arthur Centeno, Marc Gittelman, Christopher Steidle, Natalie Sacks, and Jonathan W. Simons John M. CormanJohn M. Corman More articles by this author , Eric SmallEric Small More articles by this author , David SmithDavid Smith More articles by this author , Arthur CentenoArthur Centeno More articles by this author , Marc GittelmanMarc Gittelman More articles by this author , Christopher SteidleChristopher Steidle More articles by this author , Natalie SacksNatalie Sacks More articles by this author , and Jonathan W. SimonsJonathan W. Simons More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)33201-4AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "976: Immunotherapy with GVAX® Vaccine for Prostate Cancer Improves Predicted Survival in Metastatic Hormone Refractory Prostate Cancer: Results from Two Phase 2 Studies." The Journal of Urology, 175(4S), p. 315 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 175Issue 4SApril 2006Page: 315 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information John M. Corman More articles by this author Eric Small More articles by this author David Smith More articles by this author Arthur Centeno More articles by this author Marc Gittelman More articles by this author Christopher Steidle More articles by this author Natalie Sacks More articles by this author Jonathan W. Simons More articles by this author Expand All Advertisement Loading ...

PSA-based vaccines for the treatment of prostate cancer

Prostate cancer is the second leading cause of cancer-related death among men in the USA. Vaccine strategies represent a novel therapeutic approach. One potential target for a prostate cancer vaccine is prostate-specific antigen, owing to its restricted expression in prostate cancer and normal prostatic epithelial cells. A number of prostate-specific antigen-specific epitopes have been identified that can activate cytotoxic T lymphocytes and, in turn, result in the killing of tumor targets by the peptide-specific cytotoxic T lymphocytes. Strategies employed in clinical trials consist of dendritic cell vaccines, recombinant protein and recombinant DNA vaccines, as well as viral vector delivery of vaccines. New approaches incorporating a combination of a vaccine with traditional treatments for prostate cancer are also being investigated.

Metastatic Prostate Cancer Patients Treated With GVAX?? Vaccine for Prostate Cancer Develop Immunoreactivity to Filamin: Role of Filamin in Prostate Cancer Metastasis

Metastatic Prostate Cancer Patients Treated With GVAX?? Vaccine for Prostate Cancer Develop Immunoreactivity to Filamin: Role of Filamin in Prostate Cancer Metastasis

Organic synthesis in pursuit of immunology: Large-scale synthesis of peracetylated GM2 glycosylamino acid for preparation of a multiantigenic prostate cancer vaccine

We describe herein the stereocontrolled, large-scale synthesis of peracetylated GM2 glycosylamino acid. Key features of the synthesis include a newly modified [1 + 3] coupling reaction and an olefin cross-metathesis-hydrogenation sequence. The GM2 glycosylamino acid is now ready for incorporation into a hexavalent prostate cancer vaccine construct.

Prostate Cancer Vaccine Increased Overall Survival

Prostate Cancer Vaccine Increased Overall Survival

Delayed Disease Progression after Allogeneic Cell Vaccination in Hormone-Resistant Prostate Cancer and Correlation with Immunologic Variables

There are a significant number of patients with asymptomatic hormone-resistant prostate cancer who have increasing prostate-specific antigen (PSA) levels but little or no evaluable disease. The immunogenicity and minimal toxicity associated with cell-based vaccine therapy makes this approach attractive for these patients. We have evaluated a vaccine comprising monthly intradermal injection of three irradiated allogeneic prostate cell lines (8 x 10(6) cells each) over 1 year. The first two doses were supplemented with bacille Calmette-Guérin as vaccine adjuvant. Twenty-eight hormone-resistant prostate cancer patients were enrolled. Patients were assessed clinically and PSA levels were measured monthly. Radiologic scans (X-ray, computed tomography, and bone scan) were taken at baseline and at intervals throughout the treatment period. Comprehensive monthly immunologic monitoring was undertaken including proliferation studies, activation markers, cytokine protein expression, and gene copy number. This longitudinal data was analyzed through predictive modeling using artificial neural network feed-forward/back-propagation algorithms with multilayer perceptron architecture. Eleven of the 26 patients showed statistically significant, prolonged decreases in their PSA velocity (PSAV). None experienced any significant toxicity. Median time to disease progression was 58 weeks, compared with recent studies of other agents and historical control values of around 28 weeks. PSAV-responding patients showed a titratable T(H)1 cytokine release profile in response to restimulation with a vaccine lysate, while nonresponders showed a mixed T(H)1 and T(H)2 response. Furthermore, immunologic profile correlated with PSAV response by artificial neural network analysis. We found predictive power not only in expression of cytokines after maximal stimulation with phorbol 12-myristate 13-acetate, but also the method of analysis (qPCR measurement of IFN-gamma > qPCR measurement tumor necrosis factor-alpha > protein expression of IFN-gamma > protein expression of interleukin 2). Whole cell allogeneic vaccination in hormone-resistant prostate cancer is nontoxic and improves the natural history of the disease. Longitudinal changes in immunologic function in vaccinated patients may be better interpreted through predictive modeling using tools such as the artificial neural network rather than periodic "snapshot" readouts.

Novel prime-boost combinations of PSMA-based vaccines for prostate cancer

2572 Background and Methods The development of vaccination strategies targeted to tumor antigens holds great promise for cancer therapy. Prostate-specific membrane antigen (PSMA) is an attractive candidate self-antigen for vaccination based on its expression signature. PSMA is abundantly expressed on the surface of prostate cancer cells and on the neovasculature of a wide array of other tumors, but PSMA has limited expression in normal extraprostatic tissues. In prostate cancer, PSMA expression increases with disease progression, becoming highest in high-grade, metastatic, hormone-refractory disease. Our main goals are to overcome tolerance to PSMA by active immunization and to induce recognition and rejection of tumor cells expressing PSMA. We are investigating non-replicating vaccine replicon particles (VRP) based on the alphavirus, Venezuelan equine encephalitis virus. VRP have demonstrated potency in animal models, and infect cells in the lymph nodes where the replicon drives production of large quantities of the heterologous antigen. Robust immune responses can be further amplified by VRP-induced cell apoptosis leading to cross-priming. We are also evaluating a complementary purified protein vaccine based on a novel recombinant soluble PSMA (rsPMSA) immunogen both alone and with VRP in prime-boost regimens. Results When used as single immunogens, VRP encoding full-length human PSMA elicited vigorous, durable Th1-biased cellular and humoral responses in normal BALB/c mice, whereas rsPSMA vaccines induced high levels of Th2-biased antibodies. We have now extended this analysis to human HLA-A2 transgenic mice, a more pertinent model for quantification of human Class I-restricted cellular responses, and to prime-boost regimens. Mice were immunized with VRP alone or in combination with rsPSMA boosts. PSMA-specific immune responses were measured with a panel of cellular and humoral immunoassays, including ELISPOT and intracellular cytokine staining for IFN-γ and IL-4 in T cell subsets. Conclusions Based on these translational findings, the rsPSMA protein vaccine has been advanced into a dose-escalating Phase I clinical trial in advanced prostate cancer, while the VRP-PSMA vaccine is in late-stage preclinical testing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AlphaVax, PSMA Development Company, LLC

Technology Insight: vaccine therapy for prostate cancer

The lack of effective therapies for advanced prostate cancer mandates continued development of alternative treatment strategies. Insights into the regulation of immune responses and the malignant process have facilitated the emergence of new immune-based strategies, currently under investigation in clinical trials. Like other forms of targeted therapy, cancer vaccines hold the promise of achieving cancer control without inducing overt toxicity. Many prostate cancer vaccines at different phases of development have been tested in clinical trials. Vaccination strategies under consideration include: immunization with defined antigenic preparations such as synthetic peptides, proteins or plasmid DNA; antigen-loaded dendritic cells; manipulated tumor cells; or with viral vectors engineered to express immunogenic genes. Although the underlying mechanisms of immunization may vary, all strategies share the common goal of eliciting immune responses against prostate tumor-associated antigens or of enhancing an otherwise weak antitumor response in the cancer patient. Unlocking the therapeutic potential of cancer vaccines will require a thorough understanding of cellular and molecular mechanisms that modulate the immune response. In this review, we provide an overview of vaccine-based strategies for prostate cancer therapy, discuss their mechanisms of action, and provide relevant clinical trial data.

Preclinical testing of a peptide-based, HER2/neu vaccine for prostate cancer

The HER2/neu protein is over-expressed in multiple epithelial tumors and the source of immunogenic peptides currently under investigation in vaccine trials in ovarian and breast cancers. We sought to define the correlation between HER2/neu expression and risk for prostate cancer recurrence and then determine the potential efficacy of anti-HER2/neu vaccination in prostate cancer patients at risk for recurrence. The risk for prostate-specific antigen (PSA) recurrence in 95 patients undergoing prostatectomy at the Walter Reed Army Medical Center (WRAMC) was calculated and correlated to HER2/neu expression, as determined by immunohistochemical staining. Peripheral blood lymphocytes (PBL) were then isolated from six consecutive human leukocyte antigen (HLA) A2+ patients with HER2/neu+ prostate tumors. These PBL were grown in parallel cultures and stimulated either with no peptide, HER2/neu E75 peptide, or control peptide. The cultures were compared for stimulated proliferation, induced peptide-specific cytotoxicity and tumor-specific cytotoxicity. When assessed by risk group, 69% of the high risk patients' tumors over-expressed HER2/neu compared to 47% of the intermediate risk group (p<0.05). Evaluation of the in vitro immune response of PBL isolated from six consecutive prostate cancer patients revealed a statistically significant increase in E75-stimulated lymphocytic proliferation. E75-stimulated lymphocytes demonstrated an E75-specific cytolytic response in 6/6 prostate cancer patients that increased with successive stimulations. Moreover, these E75-specific lymphocytes also demonstrated tumor-specific lysis against HER2/neu-expressing prostate cancer cell lines. The majority of prostate cancer patients at high risk for recurrence have HER2/neu expressing tumors. Hence, HER2/neu is a viable target for immunotherapeutics such as preventative immunization strategies with HER2/neu peptide vaccines.

DENDRITIC CELL BASED VACCINES: PROGRESS IN IMMUNOTHERAPY STUDIES FOR PROSTATE CANCER

No effective treatment is currently available for metastatic prostate cancer. Dendritic cell (DC) based cancer vaccine research has emerged from the laboratories to human clinical trials. We describe progress in the development of DC based prostate cancer vaccine. The literature was reviewed for major contributions to a growing number of studies that demonstrate the potential of DC based immunotherapeutics for prostate cancer. Background topics relating to DC based immunotherapy theory and practice are also addressed. DCs have been recognized as the most efficient antigen presenting cells that have the capacity to initiate naive T cell response in vitro and in vivo. During their differentiation and maturation pathways, dendritic cells can efficiently capture, process and present antigens for T cell activation. These characteristics make DC an attractive choice as the cellular adjuvant for cancer vaccines. Advances in DC generation, loading, and maturation methodologies have made it possible to generate clinical grade vaccines for various human trials. More than 100 DC vaccine trials, including 7 studies of patients with advanced prostate cancer have been reported to date. These vaccines were generally well tolerated with no significant adverse toxicity reported. Clinical responders have been identified in these studies. The new prospects opened by DC based vaccines for prostate cancer are fascinating. When compared to conventional treatments, DC vaccinations have few side effects. Improvements in patient selection, vaccine delivery strategies, immune monitoring and vaccine manufacturing will be crucial in moving DC based prostate cancer vaccines closer to the clinics.

Prostate cancer vaccine may prevent PSA, clinical progression

Prostate cancer vaccine may prevent PSA, clinical progression

A phase 2 study of an allogeneic GM-CSF gene-transduced prostate cancer cell line vaccine in patients with metastatic hormone-refractory prostate cancer (HRPC)

4565 Background A prior phase 2 study of allogeneic prostate carcinoma cell lines (PC-3 and LNCaP) genetically modified to secrete GM-CSF in 34 metastatic HRPC patients (pts) yielded a median survival of 26 months (Proc ASCO, Vol. 21:183a, 2002). The vaccine was re-engineered to secrete higher levels of GM-CSF, and this GVAX prostate cancer vaccine has been evaluated in a study designed to optimize the dose for phase 3 trials. Methods 80 metastatic HRPC pts were treated for 24 weeks in a dose-escalation trial. Doses (in millions of cells) included 200 monthly (low), 200 bi-weekly (medium), and 500 prime/300 boost bi-weekly (high). Vaccine specific antigenic protein antibodies were measured by Western blot of vaccine lysates against pts sera collected at baseline, Wk 12 and Wk 24. Type I Carboxy-terminal telopeptide (ICTP), a biologic marker useful for monitoring osteoclast activity in metastatic prostate cancer, was assayed at the same time points. PSA was collected at each treatment visit. Results 80 pts enrolled and completed treatment, and have been followed for a median of 5.4 months with no dose-limiting toxicities observed. 6/19 (32%) of pts in the high dose group showed PSA declines following repeat vaccinations. In addition, stable or decreasing ICTP levels occurred in 34/55 (62%) pts tested including all dose groups. The proportion of pts generating an antibody response to at least one cell line at Wk 12 increased with dose, with 87% of pts demonstrating an immune response in the high dose group compared with 72% and 40% in the medium and low dose groups (p=0.001, Kendall's Tau-b). Conclusions GVAX prostate cancer vaccine demonstrates immunogenicity and clinical activity in metastatic HRPC pts which appears to be dose-dependent. Stable or decreasing ICTP levels suggest osteoclast inhibition. Phase 3 trials are planned with the high dose that generated PSA declines and the optimal immunologic response rate. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cell Genesys Cell Genesys Mentor; Oncura