Over a decade ago, a disastrous trial killed research on a potential immunotherapy. Can a Regeneron bispecific revive it?

In 2006, a German biotech developed what they called a “superagonist” for CD28, a pocket on T cells that in theory could be used to stimulate their ability to fight cancer. They put it in 6 healthy volunteers, each of whom became critically ill within hours as their immune system went haywire. After that, companies backed off.

“There’s been caution that you would do anything to stimulate CD28 in a non-specific manner in humans,” explained Stephen Schoenberger, a cancer immunologist at the La Jolla Institute for Immunology.

Still, the fact remained: CD-28 was a powerful way to stimulate T cells. And 2 years ago, as Regeneron spent millions developing bispecific antibodies, they filed a patent on a method to use those bispecifics to revive that old idea.

On Wednesday, in a cover publication for Science Translational Medicines, the big biotech showed how combining that bispecific with a PD-1 therapy can both help clear solid tumors in mice and teach those mice to respond again to a tumor should it ever return. Crucially, they didn’t see the incendiary immune response seen in the 2006 trial, though that’s not a guarantee it won’t in humans.

Dimitris Skokos

“In this pre-clinical study, we laid the foundation” for a new approach, Dimitris Skokos, senior director of cancer immunology at Regeneron and the paper’s lead author, told Endpoints News. “Those two reagents do combine, they do synergize and markedly enhance the anti-tumor effect.”

This isn’t the first preclinical data Regeneron has shown for its CD-28 strategy. In January, they published data combining a bispecific for CD-28 and a bispecific for CD-3 in Science Translational Medicine. These bispecifics work by binding to both a protein on a tumor and a protein on a T cell (as opposed to a conventional antibody that only binds to one protein). There’s already evidence bispecifics can work in blood cancers in humans — including a 71% complete response rate in one 14-person Regeneron trial – and the big biotech, along with Big Pharmas such as Roche and Amgen, have made them a key part of the strategy going forward.

Schoenberger called the paper “a cautious step forward” in translating T cell-targeted bispecifics into the clinic. “If this works as advertised,” he told Endpoints, in some patients “this approach could actually produce an immunotherapeutic result that wouldn’t otherwise be possible.”

Stephen Schoenberger

The paper is in line with a broad push across biotech to enhance the effect of checkpoint inhibitors. By taking the brakes off the immune system, these inhibitors have remade cancer treatments for some patients but still have little effect for a majority of tumors.

Like all antibodies, the bispecific is shaped like a Y. In this case, one branch of the Y binds to CD-28 and the other binds to a protein specific to the tumor. Similar to turning keys in a nuclear submarine, the antibody will only activate the T cell if both Y branches bind, if it’s in reach of both CD-28 and the cancer protein. In principal, then, only T cells around the tumor will go into hyperdrive and you won’t see the kind of systemic immunological frenzy researchers saw in 2006.

Combine that with a PD-1 inhibitor and you’re both taking a brake off the immune system and accelerating it at the same time. Regeneron tested the idea in mice with prostate cancer and the PSMA antigen and epithelial cancer with the EGFR antigen. The combination halted tumor growth and improved long-term survival at a rate several times that of either drug alone. It also led to increased immunological memory; when mice were injected again with the same tumors, their immune systems were able to quickly get rid of it without intervention.

Still, Schoenberger cautioned, this is preclinical research and even in the rosiest scenarios, there are limitations. The therapy will only work for tumors that present a significant amount of a specific antigen. Not all do, and even those do could adapt, lose the antigen, and become resistant. Human tumors, he said, are thought to be less immunogenic than mouse tumors.

As for safety, he noted that while this was a markedly more specific approach, the German researchers also saw no potential safety issues in their preclinical studies. There’s only so much mice can tell you.

“You generally can’t ask a mouse how he’s feeling and what the cognitive problems might be,” he said.

Additionally, the same Regeneron bispecific study that showed a high response rate in blood cancer patients later led to two deaths from an overactive immune response. That trial combined a PD-1 with an CD3xCD20 bispecific.

Regeneron is working to get answers on this new approach in humans. Three different trials for this approach will be underway by the end of the year, they said: in ovarian cancer, in prostate cancer and in a longer list solid tumors.

Social: Dimitris Skokos (Regeneron)