Some patients with acute lymphoblastic leukemia (ALL) have gene regulation patterns that may facilitate resistance to CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy, according to research presented at the AACR Annual Meeting 2022.1
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. Researchers aimed to test whether sensitive and resistant leukemias differ in ways that may be identifiable before initiating therapy.
The researchers collected bone marrow aspirates from patients in the PLAT-02 trial (ClinicalTrials.gov Identifier: NCT02028455). The team 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, examining multiple genetic and gene expression-related signatures using a variety of methods.
The team examined samples from 7 patients whose leukemia was resistant to CAR-T therapy, and these were compared with samples from 7 patients who had leukemia that was sensitive to CAR-T therapy.
Leukemic subtype did not appear to be a factor in response. However, a distinct pattern of DNA methylation was apparent in nonresponders. It involved hypermethylated PRC2 targets in both embryonic and cancer stem cells (P =8.15 x 10-25).
Nonresponders had greater chromatin accessibility in regions related to stem cell proliferation and cell cycling (P <.0001 for each). They had chromatin accessibility patterns that were similar to those of hematopoietic stem cells (P =.037) and myeloid progenitors (P =.047).
The researchers also observed a greater frequency of cell subpopulations expressing a multi-lineage phenotype in nonresponders. In addition, cells that were unresponsive to CAR-T therapy showed significantly lower expression of genes related to antigen presentation and processing (P =.0001).
Study author Javed Khan, MD, of the National Cancer Institute in Bethesda, Maryland, noted that a change from a lymphoid to a myeloid lineage may indicate a mechanism of resistance to CD19-directed CAR-T therapy.2 He added that nonresponders with a mix of lymphoid and myeloid cell subpopulations may have 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,” Dr Khan said in a press release.
The researchers considered the results of this study to be indicative of resistance mechanisms that may be detectable prior to using CAR-T therapy.
“This study allowed us to not only identify potential clinical biomarkers, but to test the logistical feasibility of using these profiling approaches to impact patient care,” Dr Khan said. “We hope that one day, screening for this phenotype could allow clinicians to identify patients whose leukemias are unlikely to respond prior to therapy and provide alternative therapies to improve outcomes for these patients.”
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- 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