DDF 2018: How do you fix the glut of immunotherapy combo trials?

A bottleneck of immunotherapy clinical trials has put the field’s advancement somewhat on hiatus as researchers and drug companies wait for the next scientific discovery to ignite development, according to panelists at the 2018 FierceBiotech Drug Development Forum.

“I think it's fair to say that the advent of CTLA4, and then quickly thereafter PD-1 and PD-L1, were two successive lightning bolts,” said Sean McCarthy, CEO of CytomX. “Those really ignited the field of immunotherapy, with a very large number of mechanisms that have been looked at.”

But with over 1,000 clinical trials lined up to test PD-1- or PD-L1-based combinations, many of these trials may not make a lot of sense, said Tom Schuetz, CEO of Compass Therapeutics, a member of this year’s class of Fierce 15.

“I'm a medical oncologist based on my academic background, and it reminds me of the days immediately following the approval of Avastin,” Schuetz said. “The first VEGF blocker got approved, and what did we do as a field? We combined every single known therapeutic in the pharmacy with Avastin, whether it made sense or not.”

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“I think we need to do a much better job about evaluating these combinations preclinically,” he added. “I would much rather see 1,000 combination animal studies in 50,000 mice, than 1,000 clinical trials in 52,000 projected patients—it’s impossible to enroll those trials. I'm not sure what we're trying to do there.”

For the wide range of combinations being studied today, in general, the preclinical evidence has not been robust, McCarthy said, which may be a factor behind the lack of success in translations to the clinic.

“The preclinical models, the tools that we have in the lab to dissect these pathways, they're rather blunt,” he said.

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In order to usher in the next wave of immuno-oncology drugs, the field needs more potent molecules, McCarthy said, and more discovery research into biologies that can intervene in tumor growth.

One promising approach is T-cell engaging bi-specific antibodies, such as Amgen’s Blincyto. The potential lies in being able to recruit the immune system and T cells into tumor tissues, or activate the ones that are already there and turn so-called “cold tumors” hot, he said.

The problem lies, however, in their unforgiving potency and high toxicity. CytomX, a previous Fierce 15 winner, is working to mask these constructs so that they do not affect healthy tissue.

Compass is working on the same problem through its high-throughput screening platform.

“One of the things that we're trying to do is to look for targets on natural killer cells and T cells that are activated when engaged only in the presence of tumors,” Schuetz said. “We fundamentally believe in just doing a ton of preclinical experiments.”