Therapeutic PSA-targeted poxviral vaccines for prostate cancer have been well tolerated.PROSTVAC-VF treatment was evaluated for safety, prolongation of progression free of survival (PFS),and overall survival, in a randomized, controlled, and blinded phase II study. 125 patients wererandomized in a multi-center trial of vaccination series. Eligible patients had minimally symptomaticcastration resistant metastatic prostate cancer (mCRPC). PROSTVAC-VF comprises 2 recombinantviral vectors, each encoding transgenes for prostate specific antigen (PSA) and 3 immune costimulatorymolecules (B7.1, ICAM-1, and LFA3: TRICOM). Vaccinia-based vector was used for priming followedby 6 planned Fowlpox-based vector boosts. Patients were allocated (2:1) to PROSTVAC-VF +GM-CSF, versus Control empty vectors + saline injections. 2 patients received PROSTVAC-VF and 40received Control vectors. Patient characteristics were similar. The primary endpoint was PFS, whichwas similar in the two groups (P=0.6). However, at 3 years post study, PROSTVAC-VF patients had abetter overall survival with 25/82 (30%) alive, versus 7/40 (17%) controls. There was a longer mediansurvival by 8.5 months (24.5 months for vaccine versus 16 months controls);and estimated hazardratio 0.56 (95% CI 0.37-0.85);stratified log rank P=0.0061. PROSTVAC-VF immunotherapy was welltolerated and associated with a 44% reduction in the death rate and an 8.5 month improvement inmedian OS in men with mCRPC. These provocative data provide preliminary evidence of clinically meaningful benefit, but need to be confirmed in a larger Phase III study. A concurrent randomizedPhase II trial employing a recombinant poxviral vaccine provided evidence of immune responses withimproved overall survival in patients with the best immune response. This study employed the identicalvaccine in mCRPC to investigate the influence of GM-CSF with vaccine, and the influence ofimmunologic and prognostic factors on median OS. 32 patients were vaccinated once with recombinantvaccinia containing the transgenes for prostate-specific antigen (PSA) and three human costimulatorymolecules (B7.1, ICAM-1 and LFA-3, designated as TRICOM). Patients received booster vaccines withrecombinant fowlpox containing the same four transgenes. 12/32 patients showed declines in serumPSA and 2/12 showed evaluable decrease in index lesions. Median OS was 26.6 months. Patients withgreater PSA-specific T-cell responses showed a trend (p=0.055) toward enhanced survival. There wasno difference in T-cell responses or survival in cohorts of patients receiving GM-CSF vs no GM-CSF.Patients with a Halabi predicted survival of 20% in the size of large liver metastasis. This vaccinestrategy seems to be safe, is associated with both CD8 and CD4 immune responses, and has shownevidence of clinical activity. Further trials with this agent, either alone or in combination withimmunopotentiating and other therapeutic agents, are warranted. Dr. Gulley and his colleagues in theLaboratory of Tumor Immunology and Biology (LTIB) and the Medical Oncology Branch (MOB),Center for Cancer Research (CCR), NCI, have ongoing or recently completed in FY11-12 the followingcollaborative vaccine clinical trials at the NCI Clinical Center. An open label pilot study to evaluate thesafety and tolerability of PANVAC-V (Vaccinia) and PANVAC-F (Fowlpox) in combination withSargramostim (GM-CSF) in patients with metastatic adenocarcinoma, MOB, CCR, NCI. This trialemployed vectors with transgenes of both multiple tumor antigens and multiple costimulatorymolecules. This includes a breast cancer patient who initially had a PR followed by a durable CR forover 3 years. This was recently published in Clinical Cancer Research. An open label phase I study toevaluate the safety and tolerability of a vaccine (GI-6207) consisting of whole, heat-killed recombinantSaccharomyces cerevisiae (yeast) genetically modified to express CEA protein in adults with metastaticCEA-expressing carcinoma. This is a first in humans trial for this vaccine and demonstrated safety ofthis approach. This trial recently completed accrual and a manuscript will soon be submitted. An openlabel pilot study to evaluate the effect on the immune system of talactoferrin in adults with non-smallcell lung cancer (NSCLC). Immunologic response to this agent is the primary endpoint. This trial hascompleted accrual. A manuscript on this study has been submitted for publication. A phase I study todetermine the safety and feasibility of an intraprostatic PSA-based vaccine in men with prostate cancerand local failure following radiotherapy or cryotherapy or clinical progression on androgen deprivationtherapy in the absence of local definitive therapy. This study showed significant intratumoral infiltratesfollowing vaccination. A manuscript on this study has been submitted for publication. A randomized,double-blind, phase 3 efficacy trial of PROSTVAC-V/F GM-CSF in men with asymptomatic orminimally symptomatic metastatic, castrate-resistant prostate cancer has recently opened based on thepreviously mentioned phase II. This study will recruit about 1,200 men with prostate cancer inapproximately 22 countries. Dr. Gulley is the global PI for this study. Tumor regression and growth ratesdetermined in five intramural NCI prostate cancer trials: the growth rate constant as an indicator oftherapeutic efficacy. (published) IgG responses to tissue-associated antigens as biomarkers ofimmunological treatment efficacy. (published) A phase I dose escalation study of an antibody targetingdouble stranded DNA (NHS) conjugated to IL-12 is underway. A phase I dose escalation study ofyeast-brachyury is underway. Brachyury expression is involved in drug resistance, EMT and has been implicated in the metastatic process.

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Madan, Ravi A; Gulley, James L; Kantoff, Philip W (2013) Demystifying immunotherapy in prostate cancer: understanding current and future treatment strategies. Cancer J 19:50-8
Huang, Jianping; Jochems, Caroline; Talaie, Tara et al. (2012) Elevated serum soluble CD40 ligand in cancer patients may play an immunosuppressive role. Blood 120:3030-8
Madan, Ravi A; Schwaab, Thomas; Gulley, James L (2012) Strategies for optimizing the clinical impact of immunotherapeutic agents such as sipuleucel-T in prostate cancer. J Natl Compr Canc Netw 10:1505-12
Madan, Ravi A; Aragon-Ching, Jeanny B; Gulley, James L et al. (2011) From clinical trials to clinical practice: therapeutic cancer vaccines for the treatment of prostate cancer. Expert Rev Vaccines 10:743-53
Gulley, J L; Madan, R A; Schlom, J (2011) Impact of tumour volume on the potential efficacy of therapeutic vaccines. Curr Oncol 18:e150-7
Stein, Wilfred D; Gulley, James L; Schlom, Jeff et al. (2011) Tumor regression and growth rates determined in five intramural NCI prostate cancer trials: the growth rate constant as an indicator of therapeutic efficacy. Clin Cancer Res 17:907-17
Vergati, Matteo; Cereda, Vittore; Madan, Ravi A et al. (2011) Analysis of circulating regulatory T cells in patients with metastatic prostate cancer pre- versus post-vaccination. Cancer Immunol Immunother 60:197-206
Madan, Ravi A; Mohebtash, Mahsa; Schlom, Jeffrey et al. (2010) Therapeutic vaccines in metastatic castration-resistant prostate cancer: principles in clinical trial design. Expert Opin Biol Ther 10:19-28
Madan, Ravi A; Gulley, James L; Fojo, Tito et al. (2010) Therapeutic cancer vaccines in prostate cancer: the paradox of improved survival without changes in time to progression. Oncologist 15:969-75
Gulley, James L; Arlen, Philip M; Madan, Ravi A et al. (2010) Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer. Cancer Immunol Immunother 59:663-74

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