NEW YORK – Startup Xilis is anticipating a key clinical trial to read out next year in colorectal cancer, which it hopes will demonstrate the ability of its micro-organosphere drug screening tool to personalize treatments for the majority of cancer patients.
Founded in 2019 by Xiling Shen, professor of biomedical engineering at Duke University, David Hsu, physician-scientist at Duke, and Hans Clevers, professor of molecular genetics at Utrecht University, Xilis has developed a precision medicine screening platform that uses microfluidics to encapsulate patient-derived tumor cells in extracellular matrix material that mimics the original tumor environment. The resulting droplets, called micro-organospheres, or MOSs, recapitulate the biology of the original tumor cells, according to Xilis.
These MOSs can be created from a patient's tumor cells and used to test the efficacy of multiple therapeutic options within 14 days of a biopsy or surgical tumor resection. The Durham, North Carolina-based company is studying the ability of this technology to predict drug sensitivity for colorectal cancer patients in a clinical trial. Separately, it is also developing the MOS technology as a drug discovery platform.
Xilis' technology has attracted interest from investors. It raised $70 million in Series A financing last year.
The MOSs are "very striking in their ability to maintain the complexity, diversity, richness, and function of the primary tissue," Xilis Chief Operating Officer Daniel Delubac said. "[They] allow us to run predictive, functional precision medicine assays ex vivo in the laboratory to create correlations with what patients should expect in the clinic."
Upon receiving a sample from a patient, Xilis breaks the tissue up into individual cells, suspends them in a fluid matrix material with growth factors and structural molecules like collagen and glycoproteins, and adds a polymerizing agent to form spheres about 260 µm in size. MOSs comprise all of the diversity of cells found in the original tumor, in the same proportions, including fibroblasts and immune cells. According to Xilis, it has successfully produced MOSs from colon, esophagus, skin, uterus, bone, kidney, ovary, lung, and breast tumor cells with 100 percent success.
In an abstract presented at the 2021 American Society of Clinical Oncology annual meeting, Shen and colleagues from Duke University described the feasibility of using an automated imaging assay to test the potency of adoptive T-cell therapy in MOSs developed from lung cancer tumor cells. They reported that their approach has the potential to fulfill the US Food and Drug Administration's requirement for a potency assay to demonstrate reliable activity of adoptive T-cell therapies. At the same meeting, they also showed that MOSs could be used to screen for drug response in breast cancer patients and that the platform produced response patterns similar to those seen with bulk organoids.
Multicellular tumor spheroids and organoids have been used to create patient-derived models of cancer, but they have certain limitations as a personalized therapy selection tool. Organoids, invented by Clevers' laboratory in 2007, take months to derive and expand, which may not be an option for patients with advanced-stage cancer, and they require too much tissue to support screening dozens of compounds. While organoids have been used for high-throughput screening in drug discovery, due to the prolonged expansion time, the cells can lose their diversity, making them less representative of the tumor biology.
In comparison, MOSs can be produced by the thousands from a single tissue biopsy, and according to Xilis, have a high survival rate in culture. They are ready to use for drug testing within days, and can be screened against a large number of compounds in microwell plates. Moreover, because the majority of cancer patients are currently unable to benefit from genomic medicine, Delubac said, the field needs an alternative strategy to serve those patients.
Xilis is developing kits that pathologists can use to collect biopsy samples and ship them to the company for screening. "Colorectal cancer is the tip of the spear for our diagnostic assay," Delubac said. "It's the setting from which we start, and then we're planning to expand from there." The company hopes to eventually expand the use of its platform to patients with all cancer types.
In the short term, a positive readout from the colorectal cancer trial in 2023 will allow Xilis to advance the platform into validation trials. Delubac said the test will initially be introduced to personalize treatments for patients with late-stage cancer, where there is the greatest unmet need.
In the late-stage setting, Xilis envisions the MOS technology could be used either in combination with existing genomic biomarkers, or on its own, to inform treatment selection. In the future, Xilis envisions providing oncologists an integrated service, through which they can access the ex vivo and genomic insights on treatment response. Delubac said that for developing "an assay that truly changes the standard of care, we want to embed and bundle those results."
While Xilis' goal is to make the MOS platform a standard of care tool for therapy selection even for early-stage cancers, Delubac acknowledged this will take time, effort, and evidence that its technology is better at identifying the right drugs for patients compared to what they'd receive using current guidelines.
Xilis also plans to develop its MOS technology to support pharmaceutical companies with drug discovery and development, target discovery, and commercialization of drug compounds. "The therapeutic development side is just as exciting," said Delubac. "If we have those patient avatars in the laboratory that are clinically predictive of patient response … the predictivity of that tool becomes extremely useful in the context of developing new compounds."
The company took a step in that direction by recently joining the public-private consortium Oncode-PACT, led by the Netherlands-based Oncode Institute. Oncode-PACT is supported by a €325 million ($340.55 million) grant from the Dutch government to accelerate development of new cancer drugs using technologies that integrate patient data and tissues into the preclinical drug discovery stage.
In joining Oncode-PACT, Xilis will have further opportunities to demonstrate the value of its technology in treatment selection and drug development.