PROSTVAC-VF is a therapeutic poxviral vaccine-based treatment and has been previously evaluated for safety, prolongation of progression free survival (PFS), and overall survival (OS), in a randomized, controlled, and blinded phase II study published in 2010. In that study, 125 patients with minimally symptomatic metastatic castration resistant prostate cancer (mCRPC) were randomized in a multi-center trial Patients were randomized 2:1 in favor of PROSTVAC-VF which comprises of 2 recombinant viral vectors, each encoding transgenes for prostate specific antigen (PSA) and 3 immune costimulatory molecules (B7.1, ICAM-1, and LFA3: TRICOM). 82 patients received PROSTVAC-VF and 40 received control vectors. The 2 arms of the study were well balanced. The primary endpoint was PFS, which was similar in the two groups (P=0.6), however, at 3 years post study, PROSTVAC-VF patients had a better OS with 25/82 (30%) alive, versus 7/40 (17%) control group. There was a longer median survival by 8.5 months (24.5 months for vaccine versus 16 months controls); estimated hazard ratio 0.56 (95% CI 0.37-0.85); stratified log rank P=0.0061. This study demonstrated that PROSTVAC-VF immunotherapy was well tolerated and associated with a 44% reduction in the death rate and an 8.5 month improvement in median OS in men with mCRPC. These data provide preliminary evidence of clinically meaningful benefit, but need to be confirmed in a larger Phase III study. A concurrent single center study employed the identical vaccine in mCRPC to investigate the influence of GM-CSF with vaccine, and the influence of immunologic and prognostic factors on median OS. 32 patients were vaccinated once with recombinant vaccinia containing the transgenes for PSA and TRICOM. Patients received monthly booster vaccines with recombinant fowlpox containing the same four transgenes. The median OS was 26.6 months andpatients with greater PSA-specific T-cell responses showed a trend (p=0.055) toward enhanced survival. There was no difference in T-cell responses or survival in cohorts of patients receiving GM-CSF vs no GM-CSF. A recent analysis with Dr. Tsang and colleagues (LTIB) has demonstrated an association of changes in circulating regulatory T-cells and outcomes. Further trials with this agent, either alone or in combination with immunopotentiating and other therapeutic agents, are warranted. A phase III trial of Prostvac-VF in metastatic prostate cancer, largely based on the findings in the above trials will begin later in 2011. An open label phase I study to evaluate the safety and tolerability of a vaccine (GI-6207) consisting of whole, heat-killed recombinant Saccharomyces cerevisiae (yeast) genetically modified to express CEA protein in adults with metastatic CEA-expressing carcinoma has been completed this year. This is a first in human trial for this vaccine. Patients were enrolled at 3 dose levels: 4, 16, and 40 yeast units (each unit =107 yeast particles). The vaccine was administered in equal doses at 4 sites subcutaneously in bilateral inguinal and anterior chest wall regions. Vaccine was administered at 2 week intervals for 3 months, then monthly. Eligible patients were required to have a serum CEA > 5 ng/ml or >20% CEA+ positive tumor block and no autoimmune history. An expansion cohort of 10 ECOG PS 0-1 pts was enrolled to focus primarily on immune response. Patients had re-staging scans at 3 months, then bimonthly. A total of 25 patients with progressive metastatic CEA-expressing carcinoma were enrolled from April 2009 to January 2011, 22 had colorectal adenocarcinoma. Vaccine was well tolerated with no dose limiting toxicities. The most common adverse event was grade 1/2 injection site reaction. Overall, 7 patients had stabilization or declines in serum CEA after treatment. Of these patients, 5 patients had stable disease beyond 3 months and 1 is still on-going (14 +, 8, 8, 4.5 and 4 months). No anti-CEA antibodies were detected. Five out of 9 evaluable patients showed evidence by ELISPOT of CEA-specific CD8+ T-cell immune responses. 8 patients had increased CD4 effector/Treg ratio and 6 had increased NK frequency. In this trial, Saccharomyces cerevisiae-CEA demonstrated an acceptable safety profile. Although this is an advanced population of patients which may not be ideal candidates for immune-based therapy, CEA stabilizations and immune responses were seen in some patients. Further randomized studies are required to determine the clinical benefit of this vaccine. A phase II study of this drug in medullary thyroid cancer is currently being planned. A recent collaboration with Drs. James Gulley (LTIB), William Dahut (MOB), Jeffry Schlom (LTIB), Tito Fojo (MOB), and Wilfred Stein (MOB) has suggested that vaccines may alter the tumor growth kinetics in prostate cancer. This study reviewed 5 NCI prostate cancer trials including one with a vaccine (PROSTVAC-VF). Based on mathematical tumor growth models, this analysis suggests that vaccines (as compared to cytotoxic therapy) may not cause an immediate decrease in tumor volume, but over time the growth rate may slow down leading to improved long-term outcomes. This is of great importance as Protavac and other FDA-approved immunotherapy agents (Sipuleucel-T and Ipilimumab) have demonstrated overall survival improvements without changes in short-term progression. This analysis may provide the first mechanistic evidence of the underlying effects of the treatment and the apparent delayed benefits. Plans to use this change in tumor growth kinetics as a (primary) endpoint in future trials are currently in progress. Additional colloaborations with Dr. James Gulley, the Laboratory of Tumor Immunology and Biology and the Medical Oncology Branch (MOB), Center for Cancer Research (CCR), NCI, have ongoing or recently completed in FY10-11 the following collaborative vaccine clinical trials at the NCI Clinical Center. An open label pilot study to evaluate the safety and tolerability of PANVAC-V (Vaccinia) and PANVAC-F (Fowlpox) in combination with Sargramostim (GM-CSF) in patients with metastatic adenocarcinoma, MOB, CCR, NCI. This trial employed vectors with transgenes of both multiple tumor antigens and multiple costimulatory molecules. A recent amendment allowed additional patients to further analyze the efficacy of the vaccine. An open label pilot study to evaluate the effect on the immune system of talactoferrin in adults with non-small cell lung cancer (NSCLC). Immunologic response to this agent is the primary endpoint. Collaborative Trials with Extramural Cancer Centers: A phase II study of PROSTVAC-V(Vaccinia)/TRICOM and PROSTVAC-F(fowlpox)/TRICOM with GM-CSF in patients with PSA progression after local therapy for prostate cancer(Eastern Cooperative Oncology Group). A Phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM and vaccinia-CEA(6D)-TRICOM, in combination with GM-CSF and Interferon-Alfa-2B in patients with CEA expressing carcinomas(Ohio State Comprehensive Cancer Center). A Phase I study of regulatory T cell depletion with Denileukin Diftitox followed by active immunotherapy with autologous dendritic cells infected with CEA-6D expressing fowlpox-TRICOM in patients with advanced or metastatic malignancies expressing CEA (Duke Comprehensive Cancer Center). Phase I study of intravesical recombinant fowlpox-GM-CSF and or recombinant fowlpox-TRICOM in patients with bladder carcinoma scheduled for cystectomy (Cancer Institute of New Jersey, CINJ).