On a quest to revolutionize cell therapy

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Cell therapies hold tremendous promise to treat cancer, autoimmune disorders and other conditions, but they are expensive and difficult to manufacture. Illumina Ventures partner company SQZ Biotechnologies has developed a platform that could change that.

“SQZ has developed an approach to cell therapy manufacturing that could have a major impact on the industry,” said Alexis Ji, Partner at Illumina Ventures. “We are excited about the prospects of creating cell therapies that are less expensive and can be delivered to patients much more rapidly.”

Based outside Boston, SQZ (pronounced squeeze) evolved from founder and CEO Armon Sharei’s PhD project at MIT. He and colleagues were trying to push molecules inside cells, but the technique wasn’t quite working.

“We were developing a gun that could shoot materials into cells,” said Sharei. “We had a channel that cells would run through, and then we would shoot this jet of fluid to penetrate them as they went past.”

When shooting didn’t work, the team thought their projectiles might be bouncing off squishy cells. Perhaps, if they forced them to be more rigid (squeezed them), the gun would be more effective. The refinement worked but not how they expected. The squeezing process, by itself, was opening cell membranes to new materials; the gun was superfluous.

A high-throughput microfluidic chip that temporarily disrupts cell membranes to receive therapeutic cargo opens a world of possibilities. Researchers have a hard time scaling up cell therapies. Better tools could revolutionize the process.

“Cells are complex machines capable of sophisticated functions small molecules and biologics can’t do,” said Sharei. “CAR-T cells can have profound therapeutic impact, but they’re difficult to manufacture, have toxicity issues and are only applicable in narrow indications. It’s hard to engineer most cell functions, and current therapies are limited by existing techniques.”

SQZ may be poised to exceed these limitations. The company’s pipeline covers numerous conditions: cancer, type 1 diabetes, infectious diseases. The most advanced therapy, (SQZ-PBMC-HPV), now in a phase 1 trial, engineers antigen presenting cells (APCs) to induce a CD8 killer T cell response against HPV16-positive tumors, including the challenging cervical, head-and-neck, and anal cancers.

The SQZ platform could also produce cancer vaccines, which have received a lot of attention but have had little success. Sharei believes SQZ’s approach could make cancer vaccines a reality.

“APCs are the generals of the immune system – they can tell killer T cells what to target,” said Sharei. “Because we can deliver an antigen target directly to the APCs, we may have the ability to kickstart that T cell response and generate immune memory.”

SQZ is also developing a therapy against KRAS-positive tumors (SQZ-AAC-KRAS). KRAS is a common oncogene that has been virtually impossible to drug.

“Everybody has been limited to small molecule tools, but KRAS is not amenable to that,” said Sharei. “But the immune system is great at telling the difference between a mutant KRAS and a normal KRAS, which gives us an advantage.”

SQZ is also working to turn down the immune response. One therapy (SQZ-TAC-T1D) is in preclinical trials to mitigate type 1 diabetes. The same strategy could be used against multiple sclerosis, rheumatoid arthritis and other autoimmune conditions.

In addition to offering an enormous range of targets, the SQZ platform is fast, and could dramatically reduce manufacturing times.

“Our manufacturing is already an order of magnitude more cost effective than current techniques,” said Sharei. “Cell therapy costs are driven by manufacturing times, as well as the need for expensive clean rooms. We've shrunk th