Dr Davila on the Future Use of Biomarkers to Predict CAR T-Cell Therapy Resistance in LBCL

“The big question is: Can we use other biomarkers that are readily available [when assessed through] lab tests, other flow cytometry assays, and other genetic tests that…we can design [to deliver] quick and easy readout?”

Marco Davila, MD, PhD, senior vice president and associate director for Translational Research in the Department of Medicine and the Rustum Family Endowed Chair in Translational Research at the Roswell Park Comprehensive Cancer Center, discussed the clinical implications of a study investigating intrinsic tumor drivers and immune escape mechanisms associated with CD19-directed CAR T-cell therapy resistance in patients with aggressive relapsed/refractory large B-cell lymphoma (LBCL).

Davila and colleagues conducted a study to identify potential mechanisms through which genomic complexity leads to CD19-directed CAR T-cell therapy resistance in patients with relapsed/refractory LBCL. In total, 61 samples from 54 patients were collected, including 39 from the pre–CAR T-cell therapy setting, 8 from the post–CAR T-cell therapy setting, and 7 from both the pre– and post–CAR T-cell therapy settings. The investigators found that LBCL tumors likely become resistant to CD19-directed therapies because of genomic drivers that are already present at baseline. Additionally, CAR T-cell therapy resistance is driven by genomic complexity that promotes several genomic drivers that influence CD19 cell activity, the immune system, and tumor cell immunogenicity. These drivers include the biallelic inactivation of the HLA class I complex, the inactivation of natural killer cell–mediating killing mechanisms, PD-L1 alterations, and CD19 pathway alterations.

This type of analysis will likely not be generalizable to use in routine clinical practice due to the length of time it takes and the level of expertise it requires to process and analyze the findings, Davila said. However, this research has generated questions regarding the potential clinical utility of other biomarkers—including those detected through flow cytometry assays and other genetic tests—that may become more readily detectable, Davila concluded.