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EXCLUSIVE LIFE SCIENCE FEATURE leaders leaders ROUNDTABLE LIFESCIENCELEADER.COM JANUARY 2015 32 whatever size without an effort in immu- notherapy. With the consensus that immuno-oncology will constitute 80 per- cent or more of oncology drug therapy in the relatively near term, companies — particu- larly public companies — that do not claim to have immunotherapy efforts are falling out of favor with investors. Almost every company without an immunotherapy compound is trying to get access to anti- PD-1/anti-PD-L1 for a trial. Even mid-cap oncology companies are driving very hard to get into the space. Available assets in the cancer immu- notherapy space for the big and midsize oncology companies are becoming extremely scarce. For example, there are many outdated, questionably effective cancer vaccines available, but almost none of them work alone or even in com- bination. The older agents have been far surpassed by a very few newer, more elegantly designed vaccines, which are already taken by the big players or aspi- rants. There are virtually no clinical-stage checkpoint inhibitors or costimulatory molecules available, and even the preclinical ones are being heavily pursued. Thus, some companies appear to be grabbing at theories — small molecules or antibodies that affect one axis or another — that seem like a good idea in combina- tion with real immune modulators. Some of those will indeed prove to be good com- bination molecules, but may have a hard time competing with lower-cost existing alternatives. For example, low-dose met- ronomic oral cyclophosphamide, which is essentially free, nontoxic, and easily acceptable to PIs and IRBs, has generated very striking data in combination with vaccines, checkpoint inhibitors, and costimulatory molecules. The largest overlooked area among the immunotherapy companies is ablation. Despite huge support and demand from KOLs for apoptotic ablation modalities in combination with immunotherapy drugs, the big players have almost universally ignored the area. They have all also missed the huge intellectual property oppor- tunity available to them in combining immunotherapy drugs with ablative modalities. T H E M O D E R AT O R C L O S E S Roundtable moderator Llew Keltner draws some basic findings, lessons, and urgent challenges from the entire discussion in bringing this five-part series to a close. KOL s & COMPANIES IN COMPARISON One of the chief aims of this virtual round- table was to see how closely the views of key opinion leaders and company lead- ers matched — either among the peers in each group or between the two groups. One fact we discovered immediately was the extensive overlap of KOLs and companies in the cancer immunotherapy field. It is as if the intense excitement generated by the unprecedented responses in human trials drove key academic researchers to work with industry as never before to see the new agents all the way through to marketing approval. Nevertheless, the KOL community also hosts the most-guarded, even pessimistic views of immuno-oncology, just as compa- nies are the source of greatest optimism — unless, of course, they are speaking of a rival approach. (See "Companies — Convergence & Divergence.") We found a nearly uniform consensus on every side of the discussion that cancer immunotherapy is now a commercial and clinical reality, and combinations will be required for maximum clinical benefit. Some notable exceptions exist, however, including the belief, as expressed by KOL Alan Venook, that current data is insuf- ficient to prove the case. (See Part One.) We also saw a general admission that a great deal remains to be discovered about the mechanisms of action (MOAs) in the new immunotherapies, as well as MOA interactions in combination, the role of different immune-cell types, patient vari- ability, and tumor variability in regard to immune response. But the scientific uncertainties will not deter aggressive development in the field. IN THE GAME An overall picture emerges: It has become difficult to be an "oncology company" of we know predicts response to PD-1 or PD-L1 therapy. So, the potential benefit of checkpoint inhibition cuts across almost all cancers. We have to think of tumors in a new way. In looking at response to immune checkpoint therapy, the tumor's tissue and cell of origin doesn't seem to matter as much as the immunopheno- type. In particular, this means the pres- ence of the right TIL signature. Personal or broad? It is not wrong to think of our IL-12 drug as in-situ vaccination. But unlike other vac- cines, in delivering IL-12 into the tumor, we don't have to rationally choose a spe- cific antigen to suit the immune system in a particular patient. Some of the more forward-thinking vaccine technology engineers a synthetic consensus of mul- tiple antigens. We solve the problem by killing tumor cells in situ, releasing all the potential antigens present in the tumor, and letting the immune system sort out what antigens are important for response. Commercialization challenges? We are already in discussions about a combination of anti-PD-1 and our drug, and there are a lot of other immunotherapy companies thinking along the same lines. Novel-novel combos are particularly chal- lenging from a regulatory perspective. We have already seen examples of enhanced toxicity with combinations of immuno- therapies. And we certainly don't have pre- dictive models for these therapies. Intra- tumoral gene therapies like ours present a preclinical safety assessment challenge because the mouse tumor models are of such short duration, typically less than three to four weeks. As a community, we will have to work toward better solutions. We have another unique challenge: IL-12 has been shown to convert myeloid- derived suppressor cells into real APCs (antigen-presenting cells). We are in effect (not actuality) converting a tumor into a lymph node, so we don't want to kill off the tumor completely too fast. We need to apply just the right amount of IL-12, because we need the conversion to take place and leverage the local effects to drive a systemic antitumor response. COMBINATION CANCER IMMUNOTHERAPY — A VIRTUAL ROUNDTABLE By W. Koberstein