T-Cell Attacks Cancer Cell
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In the James Bond franchise, a cunning character named Q leads the fictional research and development division of the British Secret Service, which oversees top-secret field technologies. If 007 needed it, Q had already created it.

That’s the reputation that KSQ Therapeutics’ CEO, Qasim Rizvi, MD, who also goes by “Q,” strives for—but instead of an explosive alarm clock or a bagpipe flamethrower, he wants KSQ to be known as a modality-agnostic, jack-of-all-trades biopharma company that relies on a genetic screening platform known as CRISPRomics. There is, however, a significant distinction between testing a weapon in a lab or the real world and testing a therapy in vitro with cell lines and in vivo with human patients.

Nine years after its inception in 2015, KSQ has reached a significant milestone, indicating that it is no longer simply experimenting with molecular and cellular devices in a lab. KSQ announced today that the first patient had been dosed at MD Anderson Cancer Center in the first clinical trial of KSQ-001EX, the lead candidate in its autologous CRISPR/Cas9 genetically engineered tumor-infiltrating lymphocyte (eTIL) platform. The Phase I/II clinical trial for KSQ-001EX is designed for patients with melanoma, head and neck squamous cell carcinoma (HNSCC), and non-small cell lung cancer (NSCLC).

“We’ve been keeping ourselves under the radar, focusing on execution, and moving our programs forward into the clinic,” Rizvi told Inside Precision Medicine. “We’re really hoping to have a big impact on patients in the coming months.”

The Cambridge-based KSQ, named after the MIT hub at Kendall Square, was founded by William Hahn, MD, PhD, of the Broad Institute and Dana-Farber Cancer Institute, Jonathan Weissman, PhD, of MIT, Tim Wang, PhD, of MIT, and David Sabatini, MD, PhD, who was then at the Whitehead Institute and MIT.

Crisp CRISPR screening 

KSQ was founded on the belief that genome-scale insights into the genetic drivers of disease and cell function will reveal novel biology and drug development targets in a modality-independent manner. Behind that philosophy, the company created the CRISPRomics platform, which allows it to functionally interrogate every gene in the genome in the most disease-like setting possible.

“We’re not a small-molecule company; we’re not a monoclonal antibody company; we’re not a cell therapy company,” said Rizvi. “Interrogate the genome. Give the genome an opportunity to speak, and then listen and lead with science. We were in a position to not have to find the next best cell surface receptor, the next best tyrosine kinase inhibitor, the next best whatever. That’s how the pipeline came about.”

CRISPRomics identified USP1, a protein that regulates the DNA damage response (DDR), as a novel synthetic lethal target in cancers with specific types of genomic instability. As a proof-of-principle, KSQ conducted small molecule discovery and identified KSQ-4279, a first-in-class small molecule inhibitor of USP1.

“We wanted to engage the immune response to overcome cancer, but we started looking at cancer cell lines, and that’s when we first uncovered USP1,” said Rizvi. “It looked so exciting, different, and unique from other targets in that space. It would have been negligent for us not to pursue it.”

KSQ went on to conduct a Phase I clinical trial in patients with advanced solid tumors, testing two KSQ-4279 combination therapies, one with a PARP inhibitor and the other with chemotherapy. After generating clinical data, KSQ announced on July 13, 2023, that it had signed a worldwide license and collaboration agreement with Roche to develop and commercialize KSQ-4279.

Knock your SOCS off

Rizvi stated that KSQ’s real goal has been to figure out how to activate the immune system to combat cancer. The screen they wanted to do was on T cells to identify genes that could drive tumor infiltration. While applying CRISPRomics to cancer cell lines quickly produced KSQ-4279, getting the CRISPR screen to work in T cells was a completely different story.

Rizvi said, “T cells are not easy to manipulate and engineer. They’re very finicky, so we learned many lessons the hard way, but now we’ve got the secret sauce to do this. And it’s an unbiased map. It’s not like we were looking for the next best PD1 or cell receptor—knock out the gene and see what shows.”

On top of that, solid tumors present a challenge because they create an immunosuppressive microenvironment and are extremely heterogeneous. While there may be a few common antigens among patients, each solid tumor has its own distinct pattern of antigens that necessitate a tailored TIL response.

“This T-cell is going to find its way to the tumor,” said Rizvi. “You’re taking it from the tumor, and it’s polyclonal—hopefully, it’s going to find this way back. But once it’s found this way back, it gets beat up repeatedly. That harsh environment is immunosuppressive.”

So, KSQ was looking for targets in their T cell screen that could essentially turn “cold” tumors “hot”—from not eliciting an immune response to summoning the troops. When they finally got the screen to work in T cells, KSQ researchers led by chief scientific officer Micah Benson, PhD, discovered two promising targets: SOCS1 and Regnase1. Their screen also identified PD1 as a viable target, but Rizvi stated that it had far less impact than SOCS1 and Regnase-1. According to Rizvi, SOCS1 and Regnase-1 were extremely effective at driving T cells into tumors, essentially activating cold tumors.

TIL tomorrow

Keeping this in mind, KSQ pursued the eTIL approach, which received substantial clinical support mere months ago when the Food and Drug Administration (FDA) approved lifileucel (Amtagvi)—the first cancer treatment utilizing TILs and the first cellular therapy to be approved for a solid tumor, specifically melanoma. With KSQ-001EX, an eTIL with CRISPR/Cas9 inactivated SOCS1, KSQ believes they are on the right track to developing the next best-in-class treatment for a wide range of solid tumor indications.

“By taking off these brakes on this TIL, when that TIL then goes back into that tumor, it’s hopefully going to survive and be able to kill that tumor,” said Rizvi. “It’s just an elegant solution: engineer the TIL by knocking out these brakes on that T cell so it can survive in that environment.”

Though autologous, personalized therapy works differently for each individual, KSQ has been working to standardize the process for all patients. To accomplish this, KSQ formed a partnership with CTMC, a joint venture between National Resilience and MD Anderson Cancer Center, in September 2023. They collaborated on the development of a proprietary manufacturing process. The process also supports core biopsy, which eliminates the need for surgically resected material as a starting point.

“The actual editing piece, like knocking out the gene, is a very quick step in the entire manufacturing process—it doesn’t add a lot of time, challenges, or complexity,” said Rizvi. “The process that we’ve developed has been scaled. It’s been applied across multiple tumor types. So, we’re excited about where the TIL field is headed.”

It is worth noting that KSQ has yet to appear on the FDA-approved scoreboard. Since Roche acquired KSQ-4279, there has not been much of an update. So, today’s announcement of their first patient to be dosed with KSQ-001EX,  hopefully marks the start of many successful clinical journeys to come.

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