Potential genetic drivers and genomic features that may predict suboptimal response to CD19-directed chimeric antigen receptor (CAR-19) T-cell therapy in large B-cell lymphomas (LBCLs) have been identified. Most of the genomic features identified in the study, which was published in Blood, are likely reflections of the genomic complexity of the anti-tumor activities induced by CAR-19 T cells, according to corresponding author Francesco Maura, MD, of the University of Miami.
“While our findings are important, we need more information to understand how to stratify patients with LBCLs to best treatment,” he said.
According to the researchers, while response rates to CAR-19 in heavily pretreated patients with lymphoma have generally appeared promising, there is invariably a significant portion of patients who receive no benefit with these therapies and likewise experience worse survival outcomes.
Dr. Maura and researchers conducted whole-genome sequencing of 51 LBCL tumors taken from 49 patients who received CAR-19 T-cell therapy. Forty-four of the analyzed samples were obtained immediately before CAR-19 therapy was initiated.
Patients had either de novo diffuse LBCL (n=40), transformed follicular lymphoma (n=8), or transformed chronic lymphocytic leukemia (n=1). Median patient age was 65 years, and 22.4% of patients were women. Patients had received a median of two prior therapies, and 81.6% previously received platinum-containing regimens.
The presence of APOBEC mutational signatures SBS2 and SBS13, when correlated to CAR-19 response, was associated with significantly worse progression-free survival, with 92% of patients progressing (p=0.0023). In addition, SBS18 was associated with progression following CAR-19 in 81% of patients (p=0.0396).
Double minutes, chromothripsis, APOBEC mutational activity, or genomic damage resulting from reactive oxygen species were detected in 90% of relapsed/refractory lymphomas that progressed following CAR T-cell therapy, highlighting the genomic drivers or genomic complexity in these patients.
The researchers also found that patients whose disease did not respond to CAR-T therapy were strongly enriched in the recurrent 3p21.31 chromosomal deletion containing the RHOA tumor suppressor. Focal-level deletion involving 3p21.31 (RHOA) was a GISTIC (Genomic Identification of Significant Targets in Cancer) peak strongly predictive of suboptimal outcome following CAR-19 therapy (p=0.0013). The loss of RHOA was also significantly associated with worse overall survival (p=0.023).
In addition, researchers noted that pretreatment-reduced expression or mono-allelic loss of CD19 did not affect CAR-19 responses. These findings, the researchers wrote, suggest “CAR-19 therapy success and resistance are due to multiple mechanisms.”
Dr. Maura commented that if CAR T cells do not work in a subset of patients with the identified genomic features, the persisting problem remains in that there is still a lack of an alternative therapy for this population.
“We need to understand how we can use this information to stratify and develop more precise and targeted treatment,” he added. “I think we are still a little bit far from there, but there are a lot of people working hard on this, and I think at a certain point we will have more information and be able to better stratify the patient.”
A potential limitation of the study was the inclusion of only a small number of tumor samples from a small cohort of patients with LBCL.
The researchers wrote that the data generated from the study “suggest CAR T cells are not just direct cancer cell killers but also provide a gateway into the immunosuppressed tumor microenvironment to allow the host immune system to attack the tumor.” They added that the findings may likely “fuel functional studies that can establish mechanistically how complex lymphoma genomes promote milieux hostile to CAR T cells and likely other emerging immunotherapies.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
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 [published online ahead of print, 2022 Apr 27]. Blood. doi: 10.1182/blood.2021015008.
