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. Current Trials Evaluating Vaccine Combination Strategies within the project include: 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. Combining a vaccine targeting muc-1 (l-BLP 25) 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. Enzalutamide +/- PROSTVAC is currently being evaluated in 2 clinical trials based on preclinical data which suggest these therapies may have synergistic immune effects. One trial is in non-metastatic castration sensitive prostate cancer and the other is in metastatic castration resistant prostate cancer. Both of these trials will investigate how vaccine can potentially alter the growth rates in patients treated with enzalutamide and how such changes could potentially enhance clinical benefit for patients.
|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|