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Genome-Wide cfDNA Analysis May Detect CAR T-Cell Therapy Response in B-Cell Lymphoma

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NEW YORK ­– Low-coverage, genome-wide cell-free DNA measurements commonly used in noninvasive prenatal testing also appear useful in differentiating CAR T-cell therapy responders from non-responders among B-cell lymphoma patients.

Researchers with the University of California, San Diego and Laboratory Corporation of America recently showed proof of concept for the approach in a study involving 12 patients with relapsed or refractory B-cell lymphoma undergoing CAR-T therapy.

The researchers sequenced patient cfDNA at approximately 0.4X coverage. For each patient, they determined a genomic instability number, or GIN, an algorithmically derived value that quantifies the abundance of certain areas of the genome in plasma cfDNA, which served as a biomarker of treatment response.

Patients with low pre-treatment GIN and whose GIN fell over the course of treatment were more likely to achieve complete response.

Seven patients in the study achieved complete response, all of whom had significantly lower GIN values than the other patients. These seven were the only patients still alive at the last follow-up, a median of 246.5 days after beginning the study.

Five patients who failed to achieve complete response experienced an initial drop in GIN followed by a progressive rise.

Aaron Goodman, a professor of medicine at UCSD and the study's first author, explained that the idea for adapting this low-coverage cfDNA method to cancer detection and monitoring grew from observations made during prenatal testing for conditions such as Down syndrome.

"Labcorp had an interesting paper years ago where they showed that they were picking up cancer mutations or copy number alterations in their [noninvasive prenatal] testing that were suspicious of malignancy," Goodman explained, "And that's where they first realized that they could use this technology to detect cancers."

While assessing cfDNA is an established technique in monitoring cancer progression and treatment response in solid-tissue cancers, it has not been widely studied in hematologic malignancies, including CAR T-cell therapy monitoring.

"This technology is perfect for lymphoma," Goodman said, explaining that cfDNA is an attractive means of monitoring lymphomas, as these cancers behave in some ways like solid tumors and feature cells that are often more sensitive to death and therefore to releasing nucleic acids into the bloodstream.

Although this low-coverage genome-wide sequencing strategy is less sensitive than more targeted methods, it has the advantage of rapidly providing a fingerprint of copy number alterations of the whole genome, or of the whole cancer, without needing to know in advance which genomic regions to follow.

"It doesn't look at every gene," said Goodman, "but it looks at global copy number alterations."

A cfDNA-based assay can also inform physicians of changes in disease progression at finer time scales than would be possible via imaging.

"These are very aggressive malignancies," Goodman said, "where waiting a little bit longer means patients might get super sick and die."

Participants with "questionable" PET scans at 30 days post-CAR T-cell administration, for example, either maintained durable remission or experienced relapse based largely on whether their GIN values declined over treatment or not.

"Overall," Goodman and his colleagues wrote, "this study demonstrates that low pre-treatment GIN may be predictive of response, the dynamics of GIN during treatment may be correlated with clinical response, and cut-off of GIN>170 may be used to assess residual disease in patients with relapsed B-cell lymphoma treated with CAR T-cell therapy."

Goodman and his collaborators at UCSD and Labcorp are now conducting larger studies to further assess their low-coverage cfDNA strategy in hematologic cancer populations, especially among those receiving CAR T-cell therapy.

A Labcorp spokesperson commented in an email that the company recently completed another study that integrated the GIN with other genomic tests that Labcorp performs in cancer patients receiving immunotherapy, although the company did not provide further specifics.

The company is currently evaluating options for how the test may eventually be used in diagnostics and drug development, with further studies planned that will examine pre-CAR T-cell/GIN dynamics in greater detail, along with rates of change in tumor burden.

In their future studies, Goodman and his colleagues hope to show further evidence that tumor clearance and a downward GIN trend correlate with durable remissions.

"This was just a little pilot to show that we could do this and get [Labcorp] interested in doing more studies like that," Goodman said.

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