Dr Davila on CD19 CAR T-Cell Therapy Resistance in Large B-Cell Lymphoma

“We’ve done prior work that’s been published showing that the tumor microenvironment has a big role in resistance [to CD19-directed CAR T-cell therapy], but we wanted to look to see what role the tumor itself may be having in [driving] this resistance.”

Marco Davila, MD, PhD, senior vice president, associated director, Rustum Family endowed chair, Translational Research, Roswell Park Comprehensive Cancer Center, explains how intrinsic tumor drivers inform patient stratification and pretreatment decision-making for CD19-directed CAR T-cell therapy in aggressive large B-cell lymphoma (LBCL).

In an expanded cohort study evaluating intrinsic tumor drivers in CD19-directed CAR T-cell therapy resistance, the main focus was determining what may lead to poor responses for patients with LBCL receiving CD19-directed CAR T-cell therapies, Davila says. He notes that previous work has established that the tumor microenvironment plays a key role in resistance to CAR T-cell therapy. However, in this study, Davila explains that he and colleagues wanted to delve into how tumors itself could be associated with resistance.

The cohort included 54 patients with LBCL treated with CD19-directed CAR T-cell therapy; 61 whole-genome sequencing (WGS) and 54 RNA sequencing samples were analyzed by investigators. Of note, 39 samples were collected at baseline, 15 at relapse, and 7 both before and after treatment. A phylogenetic analysis was conducted on the 7 paired samples and somatic driver discovery on baseline samples, which integrated single nucleotide variants, small insertions/deletions, copy number variants, and structural variants.

Davila says looking into potential genetic mutations and genetic abnormalities within tumor cells was one major opportunity. Since the CAR T cells are targeted toward CD19, genetic pathways that could alter or destroy CD19 expression could potentially mediate resistance, according to Davila. He emphasizes that this observation is crucial, as this is a mechanism of antigen escape in acute leukemia, although this notion has been a common area for debate.