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leaders ROUNDTABLE LIFESCIENCELEADER.COM 40 NOVEMBER 2014 how to configure combinations as people become more educated about immuno- therapy and the old treatment paradigms melt away. In the studies that won its approval, ipilimumab improved overall survival in melanoma patients without a significant effect on progression, some- thing oncologists do not normally see. Many immunotherapies produce delayed responses, and sometimes patients even show shrinkage or response of their tumor at some point after the immuno- therapy has been completed. We hypoth- esize that targeted activation of an anti- tumor immune response (foot on the gas pedal) coupled with blocking immune suppression (foot off the brakes) has the potential for synergistic clinical benefit in a broad population of cancer patients. P e r s o n a l o r b r o a d ? Active immunotherapies for cancer are generally very well-tolerated, with side effects more like vaccines than other traditional anti-cancer therapies such as chemotherapy or radiation. This sug- gests they may be broadly applicable and given at some point to many cancer patients. Some therapies, such as those that require the patient's cells to be har- vested and processed outside the body, may have more limited applications. 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 ? Targeted therapies and immuno- therapies will likely be pricey at first because they are complicated to devel- op in the laboratory and require a full- blown clinical development program. Immunotherapies will initially be used in a focused way; not everyone will get immunotherapy in the early days, at least. Payers will worry about combina- tions of expensive treatments, and they have few precedents for how to keep their overall system costs in control. There will be scrutiny and demands for good, solid clinical data to support reim- bursement decisions. There is skepticism about the viabil- ity of some kinds of immunotherapy in general, and particularly in the inves- tor world. Anti-PD-1/PD-L1 success has become a lightning rod, and it seems accessible to patients as possible. However, limitations will be imposed by practicalities such as antigen expression, scalability of the approach, effect size, alternative options, etc. For cell-based approaches limitations may be greater than for more generic approaches. 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 ? Assuming we generate the needed clini- cal data on benefit/risk for any given immunotherapy or combination, the main challenges will be pricing and patient access. Particularly for combina- tions, the current pricing model will lead to very high costs for reimbursement agencies and may be prohibitive in some geographies. Building a new pricing model for combinations should improve this situation. For example, one could envision pricing a novel-novel combina- tion as a regimen and not as individu- al drugs, thus introducing substantial discounts relative to individual pricing. The industry would benefit from work- ing together to introduce new pricing models. G e n e ra l c o m m e n t ? Collaboration is going to be paramount to maximize value and speed to make combinations with immunotherapies a reality. Trends toward that are visible across the industry. Further, the evolu- tion of an immunotherapy-focused clini- cal development and regulatory para- digm, which was started by the Cancer Immunotherapy Consortium (CIC) about a decade ago, will further increase the probability of success for new therapies. B AVA R I A N N O R D I C Developing targeted cancer immuno- therapies and vaccines; lead candidate is a viral-vector antigen-targeting ther- apeutic for prostate cancer in Phase 3. JAMES BREITMEYER Division President, Cancer Immunotherapy, Bavarian Nordic Inc, and Executive Vice President, Bavarian Nordic A/S COMBINATION CANCER IMMUNOTHERAPY — A VIRTUAL ROUNDTABLE By W. Koberstein W h y c o m b i n a t i o n s ? Although a single effective immunother- apeutic agent no doubt exists, there is also great promise for taking existing and future agents into combinations. A single agent would have to have three essential actions: targeting the immune system toward the tumor, potently stim- ulating a positive immune response, and overcoming the natural resistance to the immune system many tumors express in their microenvironment. We are testing our poxvirus-based cancer immunother- apies alone and with a variety of immune checkpoint inhibitors, and are generat- ing some very exciting single agent and combination data, both in animal models and clinical trials. B a c k b o n e t h e ra p y ? The very impressive efficacy results coming in with PD-1/PDL-1 antibody blockade suggest that immune check- point inhibition may be central to cancer immunotherapy. However, one potential disadvantage to using immune check- point inhibition alone is its autoimmune side effects, reported to involve variably skin, lungs, the gastrointestinal system, and the endocrine organs. Further, some patients respond fabulously, but others do not. Patients who cannot mount an endogenous T cell immune response will not respond to checkpoint inhibition and must have their immune system specifi- cally activated and directed toward their tumor. Active cancer immunotherapy using tumor antigens presented as pro- teins or as viral or DNA vectors may fill this gap. Such combination therapy may also address the nonspecific autoim- mune effects of checkpoint inhibitors by focusing the patients' immune response on the tumor rather than on normal tis- sues. C o m b o c r i t e r i a ? In principle, each person's immune sys- tem has the potential to become educat- ed to recognize the tumor and suppress its growth with productive immunity. The timing to achieve effective antican- cer immunity may depend on the com- bination deployed. We will know better