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B Cell Gene Expression Profiling May Enable Cancer Immunotherapy CDx Test

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NEW YORK – Researchers in France have developed an analytical tool that helps identify gene expression signatures associated with patient response to cancer immunotherapies.

The method, called microenvironment cell populations (MCP)-counter, was featured in two studies published last week in Nature, which revealed an association between B cells in tertiary lymphoid structures (TLS), a part of the tumor microenvironment, and a response to immunotherapy in sarcomas and melanoma.

The results suggest a way forward for immune cell transcriptome profiling in companion diagnostics, said Wolf Hervé Fridman, a researcher at the French National Institute of Health and Medical Research (INSERM) who led the team that developed MCP-counter. His team has already begun collaborating under a multi-center, prospective clinical trial in France using TLS presence to recommend patients for treatment with Bristol Myers Squibb's Opdivo (nivolumab) and relatimab.

In the trial, Fridman's lab is using immunohistochemistry to detect TLS. The structures "are very easily assessable on tumor tissue by the pathologists," said Antoine Italiano of France's Institut Bergonié, one of the principal investigators. Italiano added that he was skeptical gene expression profiling would be the best way to detect them. But Fridman disagrees.

"I strongly believe that transcriptome-based diagnostics will be essential to predict and follow therapeutic responses, especially when only biopsies, and not large surgical pieces, are available," Fridman said. His lab is also investigating the use of single-cell sequencing to generate the B cell profiles, with proof-of-concept results expected by this summer.

MCP-counter helps evaluate immune cell infiltration of the tumor microenvironment based on gene expression profiling data. "It allows us to compare between samples regardless of richness or poorness of immune infiltration. It doesn't depend on the total number of lymphocytes," Fridman explained. His team introduced the method in a 2016 paper published in Genome Biology.

In one of the new Nature studies, an international team of researchers led by the Centre Recherche des Cordeliers in Paris found that B cells were "the strongest prognostic factor" for survival and response to immunotherapy in soft-tissue sarcoma, a larger group of tumors that was previously believed not to respond to checkpoint blockade. Using MCP-counter, they found a B cell gene expression profile that correlated with survival.

In another study looking at melanoma, researchers led by Jennifer Wargo of MD Anderson Cancer Center also used MCP-counter to observe enrichment of a B cell signature in responders and established the presence of clonally expanded B cells in those patients.

These studies, as well as another study that did not use MCP-counter, showed that B cells found in TLS were associated with a patient response to checkpoint inhibitor therapies. They also independently found gene expression profiles using RNA sequencing that were more likely to be found in patients who responded to treatment.

All three studies used gene expression analysis tools from Seattle-based NanoString Technologies. The MD Anderson- and Lund-led studies used GeoMx Digital Spatial Profiler technology. "These concurrent studies demonstrate the ability of GeoMx DSP to deliver unique and impactful biological insights that advance the field on immuno-oncology," NanoString President and CEO Brad Gray said in a statement. The other study used nCounter technology.

In recent years, cancer immunotherapy, especially PD-1 checkpoint inhibitors such as Keytruda (pembrolizumab) and Opdivo, respectively, have become front-line treatments for many cancers, including melanoma and renal cell carcinoma. They have been approved for use with companion diagnostic tests, like the Dako PD-L1 IHC 22C3 pharmDx assay, which look at tumor cell gene expression of PD-L1, a protein that helps the cells evade immune regulation. Still, only about 40 percent of patients benefit from those therapies, according to Stephen Ansell, chair of the lymphoma group at Mayo Clinic in Rochester, Minnesota. "In general, what we really need is to be able to tell who is going to benefit from immune checkpoint therapies," he said. "To date, the tests we do have are pretty rough and not as predictive as we'd like, so there is room for a better test."

In the French prospective clinical trial, only patients with TLS-positive tumor microenvironments will receive treatment. "It's one of the first prospective trials really based on an immune-based marker," Fridman said. Soft-tissue sarcomas comprise only about 1 percent of all new cancer cases, according to the National Cancer Institute. But previous studies in about half a dozen of the more than 50 different sarcoma histologies had not suggested they would respond to checkpoint inhibitors, Fridman said.

One of the new Nature studies suggested that 40 percent of sarcoma patients with the B cell signature and tertiary lymphoid structures survived past 10 months and even on to 20 months. "For sarcoma, it could be a disease-changing approach" to treatment, Fridman said.

Ansell said he was not aware of prospective studies in the US looking at using a gene expression profile of immune cells to recommend treatment. "I think it needs to be validated in a number of other studies to make people comfortable," Ansell said.

"We have to wait for the trial to be completed," Fridman said, but so far, the clinical trial data look promising. If successful, a B cell gene expression-based assay could signal a broad shift in companion diagnostic testing strategies. "We do not focus on the tumor histological subtypes anymore," Fridman said. "It's histology agnostic."