Resistance to CAR T-Cell Therapy Predicted by Epigenetic Biomarkers in Pediatric ALL

Resistance to CD19-directed CAR-T therapy was associated with molecular features identified in pediatric patients with acute lymphoblastic leukemia.

According to findings presented at the 2022 AACR Annual Meeting, resistance to CD19-directed CAR T-cell therapy was associated with molecular features identified in pediatric patients with acute lymphoblastic leukemia (ALL).1

Researchers observed 3 key characteristics of leukemic cells that do not respond to CAR T-cell therapy: DNA hypermethylation, a stem cell-like phenotype and inherent plasticity, and a decrease in cell presentation. antigen. These are independent of CD19 status and leukemia subtype, indicating a novel predictive biomarker.

“What’s most important about this is that we can detect it pre-treatment in patient samples, highlighting its potential as a response biomarker,” Katherine E. Masih, BS, NIH-Cambridge fellow at the Genetics Branch of the Center for Cancer Research at the National Cancer Institute, said at a news conference. “We hope that ultimately this can improve patient selection and eligibility for CD19 CAR T-cell therapy.”

CD19 is a common target of CAR T cells, and resistance to treatment can occur even if patients continue to show CD19 expression. Researchers explored primary non-response (PNR) to CAR T-cell therapy, which occurs in 10-20% of patients and whose causes are not fully understood. Known reasons for CAR T cell unresponsiveness include collection of dysfunctional T cells and diminished cell surface dead cell receptors.2.3

The researchers used bone marrow samples from 14 participants in the PLAT-02 trial (NCT02028455) of CD19-directed CAR-T therapy for relapsed/refractory pediatric ALL.1 These samples included those from 7 patients who had a complete response to treatment and 7 who had no response. Non-response was defined as not achieving and maintaining minimal residual disease negativity at 63 days.

Multiomics analysis of bone marrow included whole-exome sequencing, bulk cell RNA sequencing, single-cell RNA sequencing, network-based methylation analysis, and ATAC- seq (Assay for Transposase-Accessible Chromatin using sequencing).

In patients who subsequently had PNR, the researchers found epigenetic markers, including 238 regions of hypermethylated DNA, associated with inactivated genes (P = 8.15 × 10-25). These regions are known to be activated in stem cells.

ATAC-seq analysis showed increased chromatin accessibility in regions related to stem cell proliferation (normalized enrichment score [NES] = 2.31; P P

The researchers found that epigenetic differences did not lead to differences in B cell phenotype between primary susceptible patients and PNR patients. However, PNR cells showed an increase in regions associated with hematopoietic stem cells and myeloid and lymphoid progenitors. Additionally, the researchers observed a decrease in antigen presentation and processing that could lead to unresponsiveness in cells that still express CD19 (P = .0001).

These factors characterized a potential new biomarker associated with PNR that the researchers named Stem-Cell Epigenome with Multi-Lineage Potential (SCE-MLP). Masih acknowledged that the sample size of 14 patients was small and that further research on the link between SCE-MLP and PNR is needed. “We would like to see this validated in a larger cohort with more PNR cases that exist across the country,” she said.

Another potential use of SCE-MLP could be to find ways to overcome resistance to CAR T-cell therapy by combining it with targeted therapies that disrupt these epigenetic resistance factors.

Currently, the researchers hope that this research will be used to shape patient selection for CAR T-cell therapy and alternative therapies.

“If we can reliably identify responders, perhaps through screening for SCE-MLP, we can prioritize less toxic targeted therapies for our patients and improve overall outcomes for children with this devastating disease.” , Masih said.

References

  1. Masih KE, Gardner R, Chou H, et al. Multi-omics analysis identifies mechanisms of resistance to CD19 CAR T-cell therapy in children with acute lymphoblastic leukemia. Presented at the 2022 Annual Meeting of the American Association for Cancer Research; April 8-13, 2022; New Orleans, LA. Abstract 3581.
  2. Finney OC, Brakke HM, Rawlings-Rhea S, et al. CD19 CAR T product and disease attributes predict durability of leukemia remission. J Clin Invest. 2019;129(5):2123-2132. Published March 12, 2019. doi:10.1172/JCI125423
  3. Singh N, Lee YG, Shestova O, et al. Impaired death receptor signaling in leukemia causes antigen-independent resistance by inducing CAR T cell dysfunction. Discovery of cancer. 2020;10(4):552-567. doi:10.1158/2159-8290.CD-19-0813

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