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Mission Bio Working to Bring Tapestri Single-Cell Sequencing Platform to Precision Oncology

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NEW YORK – The volume of data associated with single-cell sequencing makes it an intimidating technology to bring to the clinic, but Mission Bio has taken up the challenge, as it works to demonstrate clinical utility for its Tapestri single-cell multiomics platform and sway pharmaceutical companies to test out the technology in drug trials.

Single-cell sequencing can involve different types of analysis — transcriptomic, epigenomic, proteomic, and others — to gain insights into the biology of individual cells. These methods have been used extensively in research settings to elucidate heterogeneity of solid and blood-based cancers and to identify new biomarkers that can potentially guide treatment. In one recent example, researchers performed single-cell transcriptomic profiling of more than 200,000 lung adenocarcinoma cells from 44 patients to characterize tumor cells and their microenvironments from the early to advanced stages of disease and identify new diagnostic and therapeutic targets.

It's not a great leap of imagination to envision the power of that kind of deep analysis for an individual cancer patient. Single-cell sequencing can be used to characterize the tumor microenvironment, tumor heterogeneity, spatial relationships of tumor and non-tumor cells, biomarkers in specific cells, and changes in those biomarkers over time. Experts in single-cell analysis believe that to truly provide precision oncology and identify the best treatments for patients, information at this level of granularity will be required.

A number of hurdles stand in the way of translating single-cell sequencing research techniques into clinical practice, however. The biggest challenges are the sheer quantity of data generated by these technologies, the need for standardized workflows, and the lack of studies linking single-cell sequencing data to treatment response and outcomes in cancer patients. All of that is a heavy lift, but not impossible.

Mission Bio Chief Medical Officer Todd Druley joined the San Francisco-based firm three months ago as part of the company's strategy to transition its single-cell DNA and protein sequencing platform, Tapestri, from solely a research tool to an instrument for clinical diagnosis and therapeutic selection. Druley brings to the challenge his experience at ArcherDx, which has since been acquired by Invitae, developing a ctDNA-based test with the ability to detect nearly 200 biomarkers associated with residual lung cancer in patients' blood and detect relapse years before the cancer shows up in imaging scans.

"We were very pleased with ourselves for this technical achievement," Druley said, but, "when I talked to oncologists, almost every oncologist told me they would never order this test." That's because the test did nothing but deliver bad news that was not actionable for the physician and patient and was also very expensive and unlikely to be reimbursed by insurance.

That, Druley said, was an "inflection point," where he became interested in single-cell sequencing as a solution for probing cancer cells in a way that was as actionable as it was information-dense.

Tapestri is a two-step microfluidic workflow combining a custom DNA panel of up to 1,000 amplicons as large as 200 base pairs each with a surface protein panel tailored to the specific cancer indication. The assay can read out 10,000 single cells totaling as many as 2 million bases of DNA per machine run.

Historically, Mission has focused on blood cancer research, particularly acute myeloid leukemia and multiple myeloma, but the company recently partnered with S2 Genomics to offer a solid tumor workflow including predesigned research panels for breast cancer and glioblastoma multiforme. The firm also just announced it is extending its pharma assay development services into solid tumor research.

In developing a clinical workflow for Tapestri, Mission hopes to give oncologists more granular information about a patient's cancer. A traditional gene panel or bulk NGS can identify mutations in the sample as a whole and quantify what percentage of cells have the mutations, but it can't pinpoint which mutations are present in specific cells. Without that information, Druley said, physicians are still guessing at which precision therapies to prescribe patients and in what order, and they don't always guess correctly.

"You get this game of whack-a-mole where you're just chasing different clones that you've selected for," said Druley. "What [single-cell platforms] could do is allow oncologists to treat all of these different clones at the same time." Knowing whether two or more mutations are arising in the same cell or different cells and pinpointing the emergence of resistance mutations can all help personalize treatment decisions, Druley explained.

"The long-term goal will be to look longitudinally and to ask, 'Can we follow the patients' clonal dynamics over time and is that useful to guide clinical decision-making?'" said Ross Levine, a physician-scientist at Memorial Sloan Kettering and a member of Mission's scientific advisory board.

He hopes that in the future, a doctor will be able to use single-cell analysis to not only treat a leukemia patient, for example, according to genomic markers present in the cancer but also to detect the emergence of other markers over time, similar to the way that minimal residual disease can be tracked today.

Druley said that Mission has demonstrated the technical performance of its clinical single-cell system and is now moving toward generating proof of clinical utility. The first applications will likely be for minimal residual disease in AML and multiple myeloma.

The company is also in discussions with pharmaceutical firms about how the Tapestri system can be integrated into clinical trials. Druley said they're hoping to show retrospectively using data from therapeutic intervention trials that some patients would have had better outcomes had Tapestri been available as a tool to guide treatment. The next step, then, would be to demonstrate the predictive capabilities of the single-cell technology in a prospective trial.

The idea is not necessarily a slam dunk with pharmaceutical companies due to the workflow and infrastructure needed to support the volume of data that would be produced by single-cell analysis within the context of a drug trial. "The hardest part of the sell is the infrastructure that goes around it. What's new about this is the data analysis on the back end," said Druley. "There's so much data that comes from a single machine run that it does require a certain level of computational expertise to make sense of."

Druley noted that the current iteration of the Tapestri platform is lower throughput than typical commercial laboratories. That requires finding a "sweet spot," where the number of runs is manageable in a time frame that will be clinically relevant for the patient. "We can't wait a month for samples to pile up and then run a bunch of samples," he said. The turnaround time may not be fast enough for acutely ill cancer patients. On the other hand, doing each run on-demand could be costly. "There's not a one-size-fits-all for that."

According to Levine, getting Mission Bio's platform into the hands of clinicians will require a couple of steps. To begin with, that means getting the assays into clinical and translational discovery labs, which the company is already working on. "The other thing, of course, is that you need to do the right studies to show the use case," Levine said. "You need those large datasets where you link the genomics to outcomes and to potentially actionable clinical scenarios."

In clinical practice, Levine said having access to that kind of data would go a long way in using single-cell analysis to prescribe mechanism-based therapy targeting a particular mutation in a cancer cell or its clones, monitor for relapse longitudinally and adjust treatments accordingly, and enroll patients in clinical trials earlier in their disease trajectory if their risk for therapy resistance is high.

Biomarker-informed combination therapy is widely viewed as the next step in precision oncology. Levine noted that in the future, single-cell sequencing holds promise for informing combination treatment strategies by identifying the relevant mutations in patients' cancer cells. "Curative potential largely only exists when you give combination therapy, with the notable exception of checkpoint blockade," said Levine.

One of the challenges Levine expects Mission Bio will face is figuring out how much of their analysis will be done centrally and how much infrastructure cancer centers and health systems will need to build to translate the data from the platform into actionable insights. "A place like Memorial Sloan Kettering or MD Anderson may have the ability to have large teams of bioinformaticians, but a lot of institutions don't," said Levine. "You need not only a tractable assay where the physical wet lab component can be done easily, you also need the informatics to be portable. Every indication I have is that's the solution that's being built" at Mission Bio.

The clinical value of a platform like Tapestri will also have to be demonstrated to pharmaceutical companies. "I don't think pharma, left to their own devices, without partners both in academia and in genomics, is going to be able to figure this out themselves, nor should we expect them to," Levine said.