A new study suggests that some patients with acute lymphoblastic leukemia (ALL) may have characteristics related to gene regulation that may contribute to resistance to CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy. This is based on results presented at the AACR Annual Meeting 2022 by Katherine E. Masih of the University of Cambridge in Cambridge, UK, and the National Cancer Institute in Bethesda, Maryland, and colleagues.1
CAR-T therapy targeting the CD19 receptor has been associated with high response rates in the setting of ALL, but some patients show resistance to this therapy for reasons that have not been fully understood. The researchers aimed to test whether sensitive and resistant leukemias differ in ways that may be identifiable before initiating therapy.1
The researchers collected bone marrow aspirates from patients in the PLAT-02 trial (ClinicalTrials.gov Identifier: NCT02028455) conducted at Seattle Children’s Hospital in Seattle, Washington. They grouped samples based on patients’ treatment responses, with response defined by achievement and maintenance of minimal residual disease negativity at 63 days after treatment. The researchers used a “multi-omics” approach, through which they examined multiple genetic and gene expression-related signatures using a variety of methods.1
In this study, samples were examined from 7 patients whose leukemia showed resistance to CAR-T therapy, and these were compared with samples from 7 patients with leukemia that was sensitive to therapy. A significant pattern of DNA methylation was apparent in nonresponders, which involved hypermethylated PRC2 targets in both embryonic and cancer stem cells (P =8.15 x 10-25). Leukemic subtype did not appear to be a factor in response to CD19-directed CAR T therapy.1
Analysis of chromatin using the ATAC-seq technique revealed greater chromatin accessibility in regions of sequence related to stem cell proliferation and cell cycling (P <.0001 for each). Nonresponders showed chromatin accessibility patterns that were similar to those of hematopoietic stem cells (P =.037) and myeloid progenitors (P =.047).1
In a press release associated with the research group’s presentation, Javed Khan, MD, the senior author of the study, indicated that a change from a lymphoid to a myeloid lineage may indicate a mechanism of resistance to CD19-directed CAR-T therapy. He also explained that nonresponders with a mix of lymphoid and myeloid cell subpopulations may show epigenomes that are hybrids of ALL and acute myeloid leukemia epigenomes. “Our data suggest that these leukemias, characterized by both lymphoid and myeloid-specific accessible regions, are likely less differentiated than responsive leukemias,” Khan said in the press release.2
Cells that were unresponsive to CAR-T therapy also showed significantly lower expression of genes related to antigen presentation and processing (P =.0001).1
The researchers considered the results of this study involving CD19-directed CAR-T therapy to be indicative of resistance mechanisms that may be detectable prior to using this therapy. They also suggested that adjustments to treatment approaches may be supported by the study’s findings.1
- Masih JE, Gardner R, Chou HC, et al. Multi-omic analysis identifies mechanisms of resistance to CD19 CAR T-cell therapy in children with acute lymphoblastic leukemia. Presented at AACR 2022; April 8-13, 2022. Abstract 3581.
- Leukemia patients with certain gene regulation patterns may be less likely to respond to CAR T therapy. News release. AACR; April 12, 2022.
This article originally appeared on Hematology Advisor