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Cancer Immunotherapy Combos: The Future Despite Fuzzy Road Map

Cancer immunotherapy was a hot therapeutic topic at the recent J.P. Morgan Healthcare Conference, which makes sense given the efficacy of various checkpoint inhibitors, i.e. drugs like Yervoy, nivolumab and so on. The space has seen considerable investment from large-cap companies like Bristol-Myers Squibb (BMY), Merck (MRK), Roche, and AstraZeneca (AZN). Smaller companies like Agenus (AGEN - Get Report) and private companies like CoStim are getting into the act as well. As you might expect, there are as many approaches to the use and development of checkpoint inhibitors as there are companies involved.

I had the chance to talk to a number of the companies, investors and scientists involved in cancer immunotherapy to get a sense of where the field might move over the next couple of years. Perhaps the biggest and most important takeaway was the future is not checkpoint inhibitor monotherapy. Companies are actively looking to position themselves as part of potential combinations.

Bronson Crouch, CEO of Science Seed and investor in CoStim, noted the interest in combinations comes partly from the science but also from the desire of large pharmaceutical companies and current reimbursement models. In fact, he noted that part of his interest in checkpoint inhibition came from "the interest of pharmaceutical partners prior to the company being formed."

Of course, combinations can be more than simply adding additional checkpoint inhibitors to one another. While the potential for additional efficacy exists, you also run the risk of generating a stronger autoimmune response. In fact, it was these fears that led to the recent sell-off in Bristol. Investors are not as sure that combining two checkpoints will be tolerable.

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As such, the key will be balancing the benefits of taking the breaks off of the immune system with the risks of unleashing the immune system on healthy cells. This balancing act in some ways explains why pharmaceutical companies are interested in moving the space forward as they look for the most effective and safe combinations.

Another checkpoint inhibition combination strategy being explored is the addition of therapies that better directs the immune system to tumor cells. That was the logic behind the Agenus purchase of 4-antibody and their library of six checkpoint inhibitors. Ideally, these could be combined with Agenus' in-house vaccines. While the new checkpoint inhibitors cannot immediately be used in the clinic, the company did initiate a combination trial of their cancer vaccine with Yervoy, which will provide the earliest signal of the utility of this approach.

Whether the addition of a checkpoint inhibitor is enough to rescue cancer vaccines (in general) is an open question. There is certainly a logic to the approach and previous research points to an interactive effect of cancer vaccines and checkpoint inhibition. For instance, Pardol 2012 noted that "the combination of a vaccine and a CTLA4 antibody could induce a strong enough immune response to slow tumour growth and in some cases eliminate established tumours." Clearly this needs to be replicated in human clinical trials but still represents the second major way in which the sector may develop.

A third approach would be to combine a checkpoint inhibitor with a more traditional monoclonal antibody like Rituxan. Part of the efficacy of traditional antibodies comes from Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC). This is essentially when the monoclonal antibody highlights the cancer cell as one to be attacked by the adaptive immune system.

Obviously this is an effective method but cancers are able to avoid some of the ADCC effect by hijacking checkpoints and thus dampening the adaptive immune system. The addition of a checkpoint inhibitor may short-circuit the tumors' defense and thus allow for a more robust ADCC. Last year, Innate Pharma was able to demonstrate this effect (in an animal model) when they combined lirilumab with Rituxan.

In general, it seems highly likely that checkpoint inhibitors will become a critical part of cancer treatments but how remains unknown. There are a lot of reasonable hypotheses as to the best type of combinations but not nearly enough data to handicap the space. Even if you do find a good drug class combination, the individual drugs that are best combined and how to integrate the dosing (simultaneous versus sequential, low dose versus high dose and so on) need to be further explicated. As such, the hype is likely justified when thinking about the long term potential but not all drugs and companies in the space will win.

Sobek has no positions in any stocks mentioned in this column.

David Sobek has been writing on biotech for a number of years through various outlets with a general focus on small cap oncology and antibiotics companies. He received his PhD in political science from Pennsylvnia State Univeristy in 2003 and a BA in international relations from The College of William and Mary in 1997.

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