One recurrent finding in recent large controlled immunotherapies studies for cancer has been improved overall survival (OS) without an improvement in median progression free survival (PFS). This provides a hurdle for timely completion of proof-of-concept efficacy studies. This lack of improvement in PFS with eventual demonstration of improved OS may be due to the time-lag between administering the immunotherapy and a clinically significant immune-mediated slowing of the growth-rate of the tumor. Approval of the first therapeutic cancer vaccine has conferred higher priority on the effort to augment the immunologic impact of novel experimental therapeutic vaccines with other therapies. Careful preclinical studies have highlighted the ability of standard therapies to a) kill cells in an immunologically relevant manner (immunogenic cell death) and b) change the phenotype of surviving cells to make them more susceptible to immune mediated recognition and killing (immunogenic cell modulation). This has led to rationally designed studies combining therapeutic cancer vaccines with standard therapies. These recent preclinical and clinical studies have demonstrated the ability to mount immune responses to vaccine despite standard therapies (e.g., chemotherapy). These combination studies provide a platform for testing the ability of combination strategies to impact more traditional phase 2 endpoints such as PFS. If the above hypothesis on growth rate is correct, it suggests that if one could rationally combine therapeutic vaccines (associated with delayed effects) with standard therapies (associated with early but transient decrease in tumor volume) in a manner that doesnt decrease the immune responses, then one might be able to use events such as PFS to discriminate between standard of care and combination regimens. Vaccine plus standard of care therapies Preliminary data from 2 ongoing prostate cancer trials and a breast cancer study support this hypothesis. The prostate cancer trials suggesting an improvement in time to progression (TTP) for the combination are Quadramet +/- PROSTVAC vaccine (52 vs 107 days, n=37) and flutamide +/- PROSTVAC vaccine (108 vs 192 days, n=41);and the breast cancer trial compares docetaxel +/- PANVAC vaccine with preliminary data favoring the combination (120 vs 192 days, n=48). Thus rationally designed combination studies have the potential to significantly speed up efficacy analysis in proof-of-concept efficacy studies (phase 2). This approach may be especially useful in tumors with an increasing number of therapies available that impact OS, and earlier in the disease course when follow-up for survival is more remote. Final analysis of ongoing studies may ultimately help determine the utility of this approach. Vaccine plus experimental therapies Monoclonal antibodies have been combined with vaccines for the treatment of various tumor types. In prostate cancer, a human cytotoxic T-lymphocyte antigen-4 (CTLA-4) mono-clonal antibody has been tested in combination with vaccines. CTLA-4 is a T-cell surface glycoprotein that is upregulated following T-cell activation to inhibit the immune response. Its main function is to prevent autoimmunity by regulating the bodys immune activity. T cells express two counteracting receptors on their cell surface CD28 and CTLA-4. Both bind to the same ligands or costimulatory molecules on the surface of APCs (B7.1 and B7.2, also known as CD80 and CD86). Binding of these costimulatory molecules to CD28 activates T cells, while interacting with CTLA-4 inhibits T-cell stimulation. Blocking CTLA-4 with a neutralizing antibody has been shown to sustain and potentiate immune responses. We have recently completed a safety study of PROSTVAC combined with ipilimumab, which blocks negative costimulation. Up to 10 mg/kg of ipilimumab was safely administered with a vaccine that enhances positive costimulation. Immune-related adverse events were similar in proportion and gradeto those previously reported with ipilimumab alone. Furthermore, while the median predicted survival was about 18 months based on a validated nomogram, actual median OS exceeded 34 months in this phase I study. Dr. Gulley and his colleagues in the Laboratory 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 following combination vaccine clinical trials at the NCI Clinical Center. A randomized Phase II trial combining vaccine therapy with PROSTVAC/TRICOM and Flutamide, vs. Flutamide alone in men with androgen insensitive non metastatic (D0.5) prostate cancer, MOB, CCR, NCI. This was the first randomized trial to combine a vaccine with this second-line hormone therapy in D0.5 prostate cancer patients. A phase I Trial of a PSA based vaccine and an anti-CTLA-4 antibody in patients with Metastatic Androgen Independent Prostate Cancer. This trial is the first clinical trial to combine an anti-CTLA-4 antibody and a vector-based vaccine in prostate cancer. A manuscript on this study has been published. A randomized phase 2.5 study of 153Sm-EDTMP (Quadramet) with or without a PSA/TRICOM vaccine in men with androgen-insensitive metastatic prostate cancer, MOB, CCR, NCI. This trial is the first clinical trial to combine vaccine with a bone seeking radionuclide for use in patients with androgen independent prostate cancer. Formal protocol specified interim analysis presented at ASCO 2012 and is being written up for publication. A randomized Pilot Phase II study of Docetaxel alone or in combination with PANVAC-V (vaccinia) and PANVAC-F (fowlpox) in with metastatic breast cancer. MOB, CCR, NCI. This is the first randomized trial to combine vaccine with Docetaxel in this breast cancer patient population. This trial recently completed accrual and results are being written for publication. Long-term follow-up of prostate cancer patients treated with vaccine and definitive radiation therapy. (recently published) Two studies have recently been started combining a newly approved androgen receptor inhibitor (enzaulatamide) with or without PSA-TRICOM vaccine in patients with either rising PSA but no radiographic evidence of disease, or patients with metastatic castration resistant prostate cancer. Collaborative Trials with Extramural Cancer Centers 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) This trial recently completed accrual. We are currently in discussions with the RTOG on a multi-center cooperative group study of Alpharadin and PSA-TRICOM for patients with bone metastasis based on the preliminary results of the Quadramet with or without vaccine study.

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Bilusic, Marijo; Madan, Ravi A; Gulley, James L (2017) Immunotherapy of Prostate Cancer: Facts and Hopes. Clin Cancer Res 23:6764-6770
Gulley, James L; Berzofsky, Jay A; Butler, Marcus O et al. (2017) Immunotherapy biomarkers 2016: overcoming the barriers. J Immunother Cancer 5:29
Gulley, James L; Rajan, Arun; Spigel, David R et al. (2017) Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial. Lancet Oncol 18:599-610
Madan, Ravi A; Gulley, James L (2017) Prostate cancer: Better VISTAs ahead? Potential and pitfalls of immunotherapy. Nat Rev Urol 14:455-456
Madan, Ravi A; Gulley, James L (2017) Prostate cancer immunotherapy: the path forward. Curr Opin Support Palliat Care 11:225-230
Rajan, Arun; Kim, Chul; Heery, Christopher R et al. (2016) Nivolumab, anti-programmed death-1 (PD-1) monoclonal antibody immunotherapy: Role in advanced cancers. Hum Vaccin Immunother 12:2219-31
Madan, Ravi A; Karzai, Fatima H; Ning, Yang-Min et al. (2016) Phase II trial of docetaxel, bevacizumab, lenalidomide and prednisone in patients with metastatic castration-resistant prostate cancer. BJU Int 118:590-7
Madan, Ravi A; Gulley, James L; Dahut, William L (2016) Radium-223 in prostate cancer: emitting the right signals. Lancet Oncol 17:1186-7
Heery, Christopher R; Madan, Ravi A; Stein, Mark N et al. (2016) Samarium-153-EDTMP (Quadramet®) with or without vaccine in metastatic castration-resistant prostate cancer: A randomized Phase 2 trial. Oncotarget 7:69014-69023
Wattenberg, Max M; Fong, Lawrence; Madan, Ravi A et al. (2016) Immunotherapy in genitourinary malignancies. Curr Opin Urol 26:501-7

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