Reprogramming the tumor microenvironment to help detect and fight cancer
President and CEO: Michael Aberman
Scientific founders: Laurie Glimcher, MD; Juan Cubillos-Ruiz, PhD; Sarah Bettigole, PhD
Based: New York
Clinical focus: Its lead inhibitor targets IRE1-alpha, a cellular stress pathway contributing to immunity in the solid tumor microenvironment.
The scoop: Quentis is taking a new tack on a long-considered target linked to poor prognoses in several solid cancers: the endoplasmic reticulum (ER) stress pathway. Part of the cell’s unfolded protein response—where, under the harsh conditions found in tumors, proteins begin folding improperly within the cell—the ER pathway activates processes that either restore balance by clearing out malformed proteins or trigger cell death.
But when scientists looked for direct anti-cancer effects in one of the primary ER stress-signaling enzymes, IRE1-alpha, the results were disappointing. “When people went after it, they discovered it's not killing tumor cells in the typical way that cytotoxics are tested, such as in petri dishes with enough nutrients,” Quentis President and CEO Michael Aberman said.
The researchers behind Quentis found, however, that knocking out IRE1 in the broader tumor microenvironment boosted T-cell function and enhanced the abilities of immune response-triggering dendritic cells, thus shrinking tumors in mouse models.
What makes Quentis fierce: Despite advances in immunotherapy and the excitement about checkpoint inhibitors, complete response rates still lag. Companies are sifting patient populations for the right subgroups to target and casting about for drug combinations that just might work.
But designing an antibody, an inhibitor or a CAR-T cell to directly attack cancer may only get you so far, said Laurie Glimcher, president of the Dana-Farber Cancer Institute.
“If you think of the tumor as a castle, the microenvironment is a very hostile neighborhood,” Glimcher said. “It's a moat around that castle […] You can activate your T cells—you can put in CAR-T cells, or you can activate them endogenously with checkpoint blockers—but if they can't get into the site of the tumor, then they just don’t work.”
Glimcher serves as the scientific founder of Quentis, her first commercial spinout. “These data were just so compelling for us,” she said. “This is a field that my lab has been working on for 20 to 30 years.”
Glimcher’s lab stumbled quite randomly into discovering the incredibly effective and druggable IRE1 pathway. After isolating the key transcription factor working that pathway, the researchers spent years studying its function, eventually finding that inhibiting it helped kill triple-negative breast cancer cells and other tumors.
What truly surprised them, however, was that inhibiting the pathway also reprogrammed several different cell types in the tumor microenvironment, as well as relevant immune cells.
“Once that paper came out, we really felt we had a tiger by the tail,” Glimcher said. “One of the great things about inhibiting this pathway is that it's a double whammy. Once you inhibit it, it promotes tumor death at the same time it activates the immune system.”
Glimcher believes that more discovery research into the tumor microenvironment may help uncover why some patients respond to immunotherapies and others do not, as well as provide a wealth of novel targets to go after.
“I think we have a goldmine that we can interrogate,” Glimcher said. One of her pharma colleagues, in fact, told her their company was so inspired by that paper, it started a separate division specifically to study ER stress pathways.
In another gold rush, Quentis has set up shop in the burgeoning biotech hub in New York City, staking its claim in the Alexandria Center for Life Sciences as other startups and researchers migrate to the city. While the area has seen fits and starts of biotech activity in the past, Aberman believes New York has passed a tipping point, and will eventually become as much a destination as Boston or San Francisco.
In the city, researchers and CEOs are beginning to cross-fertilize and share their ideas, Aberman said. And as Quentis staffs up—with the help of its $48 million series A raise in February—the company is finding no shortage of talent.
“There's a lot of people who were originally at Big Pharma or Connecticut-based biotech companies that may be downsizing,” Aberman said. While some may feel the need to relocate for their career's sake, “there's a lot of people who would love to get back to New York ... For every job offer we put up, we’re getting great résumés in terms of the scientific talent.”
Investors: Versant Ventures, Polaris Partners, AbbVie, Alexandria Venture Investments and the investment arm of Empire State Development, New York Ventures