Several genomic factors appear to be associated with resistance to antiCD19 chimeric antigen receptor (CAR) T-cell (CAR-19) treatment in some patients with large B-cell lymphomas (LBCLs), including diffuse large B-cell lymphoma (DLBCL), according to a whole-genome sequencing (WGS) study published in the journal Blood.
The WGS identified several pretreatment factors, including mutational activity in apolipoprotein B mRNA editing enzyme, catalytic (APOBEC) polypeptide, 3p21.31 chromosomal deletions in the RHOA tumor suppressor gene, complex structural variants, and damage from reactive oxygen species (ROS), which were predictive of CAR-19 resistance among patients.
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Of the 29 patients in the study with relapsed/refractory lymphomas, 26 (90%) had either RHOA deletions, APOBEC mutational activity, ROS damage, or complex structural variants including double minutes or chromothripsis.
“Most of these genomic features do not appear to directly cause a dysregulation of a distinct pathway or gene function, but rather reflect the complexity and ongoing instability of certain genomes,” the authors wrote.
“We should not see these genomic features as being in opposition to the immune microenvironment, but rather, these data suggest that LBCL CAR T-cell resistance is driven by a complex interplay between immune microenvironment and cancer cells, and this effect must be accounted for in future studies,” the study team continued.
The researchers acknowledged that WGS is highly impractical for use in the clinical setting as well as many research settings since it requires fresh-frozen tumors and matched germline DNA. They did mention that certain indicators such as APOBEC mutational signatures could potentially be used in these settings since they can be established with only exome data.
A total of 49 patients with LBCL were included in the study and had tumor biopsy specimens collected. Of the patients, 40 had de novo DLBCL, 8 had follicular lymphoma and 1 had transformed chronic lymphocytic leukemia. Response without progression was observed in 18 patients, relapse was observed in 23 patients, and refractory disease was observed in the remaining 8 patients.
Jain MD, Ziccheddu B, Coughlin CA, et al. Whole-genome sequencing reveals complex genomic features underlying anti-CD19 CAR T-cell treatment failures in lymphoma. Blood. Published online August 4, 2023. doi:10.1182/blood.2021015008