Companies are trying all kinds of combinations to make checkpoint inhibitors work for more people, including pairing them with cancer-killing viruses, engineered cytokines or even other checkpoint blockers. Medicxi’s latest bet is Monopteros Therapeutics, a biotech working on a treatment to reprogram T cells in the tumor microenvironment to jump-start an immune attack in cancer patients who otherwise would not respond to checkpoint inhibitors.
The company emerges from stealth with $20 million from Medicxi and an asset licensed from Helmholtz Zentrum München in Germany. The treatment, MPT-0118, inhibits an enzyme called MALT1 that Monopteros co-founder Thorsten Mempel, M.D, Ph.D., discovered plays a key role in tumor-associated T cells.
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“We all have regulatory T cells—if not, we would all have autoimmune disease and we would be very, very sick,” said Peter Keller, CEO of Monopteros. “They’re good guys in general; it’s only in the tumor that they’re not good guys because in the tumor they supporess the immune response. It’s the reason why checkpoint inhibitors like Keytruda and Opdivo don’t work well in many solid tumors.”
Drugs like Merck’s Keytruda and Bristol Myers Squibb’s Opdivo work by releasing immune checkpoints, or “brakes” that stop T cells from attacking tumors. But in some cancers, that doesn’t work, because regulatory T cells, or Tregs, become immunosuppressive in the tumor microenvironment.
“Immunosuppressive regulatory T cells are preventing many patients with solid tumors from realizing the durable benefit from cancer immunotherapy currently achieved by a minority of patients,” said Keith Flaherty, M.D., director of developmental therapeutics at the Massachusetts General Hospital Cancer Center and chairman of the Monopteros clinical advisory board, in a statement.
“MPT-0118 demonstrates the potential to reprogram Tregs, which can be an essential mechanism for increasing the response rates of checkpoint inhibitors for patients with these common cancer types,” Flaherty added.
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Mempel, a professor at Massachusetts General Hospital and Harvard Medical School discovered that Tregs in the tumor microenvironment have an increased reliance on MALT1 and that blocking MALT1 stops them from suppressing the immune response and spurs them to produce the inflammation-promoting cytokine inteferon-gamma.
Where others have tried to deplete Treg levels in the tumor microenvironment or prevent Tregs from getting into the tumor in the first place, Monopteros aims to “make the bad guys good guys,” Keller said.
“We don’t have to be antigen-specific. Any regulatory T cell in the tumor microenvironment can be destabilized and used to our advantage,” he said.
Though the compound has shown activity as a single agent, the company is laser-focused on developing for combinations with PD-1 drugs. It may consider other combinations later on.
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“It makes a lot of biological sense to combine; I think the future in solid tumors that are so hard to treat is combination therapies. The question is: what are the right combinations?” Keller said.
Since it started operating in early 2019, Monopteros has pushed MPT-0118 into a phase 1/1b dose escalation and cohort expansion clinical trial. And it’s done so with a lean, mean team of one.
“It’s a totally virtual team. I’m the only employee,” Keller said, adding that he’s had help along the way from collaborators and consultants. He hopes to build the team “at some point,” but said the company’s immediate focus is the clinical trial.
Once Monopteros lands on a recommended phase 2 dose and understands the biological activity of its drug, it can start to think about other things, like partnering, raising more money and expanding the company, Keller said.