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leaders ROUNDTABLE LIFESCIENCELEADER.COM 42 NOVEMBER 2014 leaders everyone is scrambling to buy the next checkpoint antibody, push it into the clin- ic faster, or try for breakthrough designa- tion. But in other areas, such as active immunotherapy or cancer vaccines, there is still skepticism, particularly among investors and potential commercial part- ners. Another hurdle is that some physi- cians and investigators understand how immunotherapy may be different from chemotherapy, hormone therapy, or radia- tion; others do not. The knowledge base around immuno-oncology for cancer ther- apy is expanding exponentially as more clinicians treat patients with this novel treatment paradigm. TA K E D A / M I L L E N N I U M Exploring development of next-generation immunotherapies. MANFRED LEHNERT, M.D. VP and Head, Innovation Oncology Therapeutic Area Unit, Takeda Pharmaceuticals W h y c o m b i n a t i o n s ? The major benefit of single agents has been limited to a subset of 20-40 percent of patients in certain diseases. There is a strong mechanistic rationale for combina- tions, and there is preclinical and early clinical data to support that. E s s e n t i a l c o m p o n e n t s ? At this point, anti-PD-1 or anti-PD-L1 would seem the backbone of clinical combination development. But this may well change in the future, when we bet- ter understand the clinical activity and safety profile of the many other agents and approaches that are in development. It may well be that optimal immune-ther- apy combination will depend on disease context (disease type and/or stage), and may be guided by molecular information from tissue (tumor and/or adjacent nor- mal) and/or blood. C o m b o c r i t e r i a ? This will be largely driven by a mechanis- tic and scientific rationale and differential clinical benefits. It would seem inconceiv- able that oncologists may consider com- bining individual immune-therapeutics in routine clinical practice without robust benefit-risk evidence from well conducted clinical trials. P e r s o n a l o r b r o a d ? It seems likely that these two general approaches are not mutually exclusive, and each will play an important role in the same or different diseases. G e n e ra l c o m m e n t ? The field of therapeutic cancer vaccines has remained largely unsuccessful to date. But this may change through improved vaccine technology, personalization of vaccine therapy, and perhaps most impor- tantly, concomitant or sequential combi- nation with therapies that break immune tolerance. I M M U N O VA C C I N E Early clinical-stage development of DepoVax vaccine adjuvanting platform and product candidates for cancer therapy. MARC MANSOUR, PH.D. Chief Executive Off cer Note: The company's science advisor, Neil Berinstein, M.D., Director of Translational Research at the Ontario Institute for Cancer Research (OICR), and Marianne Stanford, Ph.D., Director of Research, contributed to Dr Mansour's response. Dr. Berinstein also participated in the KOL discussions in Parts One and Two of this series. E s s e n t i a l c o m b i n a t i o n c o m p o n e n t s ? We need at least two components to "drive" effective cancer immunotherapies: We need a therapy, such as an effective cancer vaccine, to "push the accelerator," or facilitate anti-tumor immune respons- es, and a component to "release the brakes," or limit the immune suppressive forces that impair generation or effective- ness of the anti-tumor responses. Thus, we need to generate or provide effective tumor-specific T cells and also provide active but safe immunomodulators such as checkpoint inhibitors. C o m b o c r i t e r i a ? Ideally, specific immunotherapy combi- nations will eventually be selected based upon the patient's tumor-expression pro- file and immune status. Initially, we will likely select treatments based upon data from trials that demonstrate the effec- tiveness of certain immune therapies and combinations in specific tumor cancer types and tumor stages. The biologic dif- ferences between tumor types and stages of tumor progression will prevent extrap- olation into additional clinical indications without the relevant trials. Regulatory authorities will likely take this perspec- tive until proven otherwise. P e r s o n a l o r b r o a d ? There are many types of personal- ized medicine used in clinical practice today, including surgery and autologous or allogeneic transplantation. Thus, it is likely that effective cell therapy or other immune therapies will be made available clinically. The more significant concern is how to reduce toxicities, particularly in early, high-risk clinical situations where risk of recurrence is high but the patient only presents microscopic disease. We need well-tolerated therapies, and off-the- shelf combination therapies will likely be more applicable than cell-based therapies such as CAR. C o m m e r c i a l i z a t i o n c h a l l e n g e s ? The evolving science in cancer immu- notherapy has a significant impact on clinical trial design, particularly in the areas of analysis of clinical responses and the appropriate selection of patients to enroll in trials. We must identify the optimal immune modulators and immune-modulator combinations for the clinical indication being addressed. The issue of clinical responses to immu- notherapy has been partially addressed through the irRC, or immune related RECIST criteria, but the uptake of irRC in pivotal trials has been slow. Preliminary COMBINATION CANCER IMMUNOTHERAPY — A VIRTUAL ROUNDTABLE By W. Koberstein