One recurrent finding in recent large controlled immunotherapies studies for cancer has been improvedoverall survival (OS) without an improvement in median progression free survival (PFS). This providesa hurdle for timely completion of proof-of-concept efficacy studies. This lack of improvement in PFSwith eventual demonstration of improved OS may be due to the time-lag between administering theimmunotherapy 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 augmentthe immunologic impact of novel experimental therapeutic vaccines with other therapies. Carefulpreclinical studies have highlighted the ability of standard therapies to a) kill cells in animmunologically relevant manner (immunogenic cell death) and b) change the phenotype of survivingcells to make them more susceptible to immune mediated recognition and killing (immunogenic cellmodulation). This has led to rationally designed studies combining therapeutic cancer vaccines withstandard therapies. These recent preclinical and clinical studies have demonstrated the ability to mountimmune responses to vaccine despite standard therapies (e.g., chemotherapy). These combinationstudies provide a platform for testing the ability of combination strategies to impact more traditionalphase 2 endpoints such as PFS. If the above hypothesis on growth rate is correct, it suggests that if onecould 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 theimmune responses, then one might be able to use events such as PFS to discriminate between standardof care and combination regimens. Vaccine plus standard of care therapies Preliminary data from 2ongoing prostate cancer trials and a breast cancer study support this hypothesis. The prostate cancertrials 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 datafavoring the combination (120 vs 192 days, n=48). Thus rationally designed combination studies havethe 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 thatimpact OS, and earlier in the disease course when follow-up for survival is more remote. Final analysisof ongoing studies may ultimately help determine the utility of this approach. Vaccine plus experimentaltherapies Monoclonal antibodies have been combined with vaccines for the treatment of various tumortypes. In prostate cancer, a human cytotoxic T-lymphocyte antigen-4 (CTLA-4) mono-clonal antibodyhas been tested in combination with vaccines. CTLA-4 is a T-cell surface glycoprotein that isupregulated following T-cell activation to inhibit the immune response. Its main function is to preventautoimmunity by regulating the bodys immune activity. T cells express two counteracting receptors ontheir cell surface CD28 and CTLA-4. Both bind to the same ligands or costimulatory molecules on thesurface of APCs (B7.1 and B7.2, also known as CD80 and CD86). Binding of these costimulatorymolecules 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 immuneresponses. 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 avaccine that enhances positive costimulation. Immune-related adverse events were similar in proportionand grade to those previously reported with ipilimumab alone. Furthermore, while the median predictedsurvival was about 18 months based on a validated nomogram, actual median OS exceeded 34 monthsin this phase I study. Dr. Gulley and his colleagues in the Laboratory of Tumor Immunology andBiology (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 theNCI Clinical Center. A randomized Phase II trial combining vaccine therapy withPROSTVAC/TRICOM and Flutamide, vs. Flutamide alone in men with androgen insensitive nonmetastatic (D0.5) prostate cancer, MOB, CCR, NCI. This was the first randomized trial to combine avaccine 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 IndependentProstate Cancer. This trial is the first clinical trial to combine an anti-CTLA-4 antibody and avector-based vaccine in prostate cancer. A manuscript on this study has been published. A randomizedphase 2.5 study of 153Sm-EDTMP (Quadramet) with or without a PSA/TRICOM vaccine in men withandrogen-insensitive metastatic prostate cancer, MOB, CCR, NCI. This trial is the first clinical trial tocombine vaccine with a bone seeking radionuclide for use in patients with androgen independentprostate cancer. Formal protocol specified interim analysis presented at ASCO 2012. A randomizedPilot Phase II study of Docetaxel alone or in combination with PANVAC-V (vaccinia) and PANVAC-F(fowlpox) in adults with metastatic breast cancer. MOB, CCR, NCI. This is the first randomized trial tocombine vaccine with Docetaxel in this breast cancer patient population. This trial recently completedaccrual. Long-term follow-up of prostate cancer patients treated with vaccine and definitive radiationtherapy. (recently published) A pilot safety trial investigating a vector-based vaccine targetingcarcinoembryonic antigen in combination with radiotherapy in patients with gastrointestinalmalignancies metastatic to the liver. (recently published) In the last year a trial has begun enrolling at the NCI combining a vaccine targeting muc-1 (Stimuvax) and combining that with standard radiation and hormonal therapy for high risk prostate cancer. This is a broad collaboration involving MOB, LTIB, UOB, ROB, and MIP. The primary endpoint of this trial will evaluate immunologic response to this vaccine combination. Additional combination trials are being planned using PSA-TRICOM with emerging hormonal therapies and radiopharmaceuticals in prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011281-03
Application #
8553078
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2012
Total Cost
$161,730
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Huen, Ngar-Yee; Pang, Alan Lap-Yin; Tucker, Jo A et al. (2013) Up-regulation of proliferative and migratory genes in regulatory T cells from patients with metastatic castration-resistant prostate cancer. Int J Cancer 133:373-82
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
Singh, Nishith; Madan, Ravi A; Gulley, James L (2013) Ipilimumab in prostate cancer. Expert Opin Biol Ther 13:303-13
Bilusic, Marijo; Madan, Ravi A (2012) Therapeutic cancer vaccines: the latest advancement in targeted therapy. Am J Ther 19:e172-81
Madan, Ravi A; Mohebtash, Mahsa; Arlen, Philip M et al. (2012) Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol 13:501-8
Kamrava, M; Kesarwala, A H; Madan, R A et al. (2012) Long-term follow-up of prostate cancer patients treated with vaccine and definitive radiation therapy. Prostate Cancer Prostatic Dis 15:289-95
Madan, Ravi A; Bilusic, Marijo; Heery, Christopher et al. (2012) Clinical evaluation of TRICOM vector therapeutic cancer vaccines. Semin Oncol 39:296-304
Madan, Ravi A; Heery, Christopher R; Gulley, James L (2012) Combination of vaccine and immune checkpoint inhibitor is safe with encouraging clinical activity. Oncoimmunology 1:1167-1168
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
Bilusic, Marijo; Heery, Christopher; Madan, Ravi A (2011) Immunotherapy in prostate cancer: emerging strategies against a formidable foe. Vaccine 29:6485-97

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