NEW ORLEANS — A novel biomarker based on stem-cell epigenetic signatures may help identify children and young adults with relapsed or refractory acute lymphoblastic leukemia (ALL) who would be unlikely to benefit from chimeric antigen receptor T-cell (CAR T) therapy.

The researchers coined the term “stem-cell epigenome with multilineage potential” (SCE-MLP) for the novel candidate biomarker for antigen-independent, primary nonresponse to CD19-directed CAR T therapy in children with ALL.

The SCE-MLP signature is characterized by 238 differentially methylated regions, an associated stem cell–like phenotype, inherent plasticity, the maintenance of a B-lineage ALL phenotype that also harbors characteristics of myeloid cells and stem cells, and decreased expression of genes involved in antigen presentation and processing, the team reported.

“Most importantly, this can be detected prior to therapy, so this highlights its potential use as a biomarker for response, and we hope that this could potentially improve patient selection and eligibility,” said lead author Katherine E. Masih, BS, from the Genetics Branch in the Center for Cancer Research at the National Cancer Institute (NCI).

The new findings also point to potential strategies for overcoming resistance in these patients, Masih commented. For example, pretreatment with epigenetic modulators such as hypomethylating agents could make SCE-MLP ALLs sensitive to CAR T therapy.

The new findings were presented in a mini-symposium and were highlighted at a media briefing here at the American Association for Cancer Research (AACR) Annual Meeting 2022.

“I think it’s incredible work and incredible potential, so we need more studies in this area,” commented Ana Maria Lopez, MD, MPH, professor and vice chair of medical oncology and chief of medical services at Sidney Kimmel Cancer Center–Jefferson Health New Jersey in Washington Township, New Jersey.

Lopez, who moderated the briefing, commented that the biomarker is valuable not only because of its ability to identify patients who are unlikely to benefit from CAR T therapy but also because it can identify patients who will respond to CAR T therapy, for whom it may be possible to deescalate therapy.

Study Details

Masih and colleagues noted that most research into resistance mechanisms against CAR T therapy has focused on relapse after an initial response. They were interested, however, in the problem of primary nonresponse, defined as progressive CD19 positivity despite CD19 direct CAR expansion within 63 days of infusion.

“We asked the question, what characterizes patients who do not respond to CD19 CAR T-cell therapy? And we hypothesized that primary nonresponders to CD19 CAR T-cell therapy have a distinct leukemia when compared to patients who do respond and that these differences can be detected prior to treatment,” Masih said.

To test this hypothesis, they examined leukemia samples from 14 children and young adults with B-ALL who underwent treatment at Seattle Children’s and who received with CD19 CAR T therapy in the PLAT-02 clinical trial. In this trial, patient responses were tracked by flow cytometry.

The samples were then stratified according to response or lack of response. Samples from patients who did not demonstrate expansion of CD19 CAR T cells were excluded on the assumption that the CAR T product itself was faulty.

The investigators also subjected pretreatment bone marrow samples to a large panel of analyses, including genomics, transcriptomics, epigenomics, and also ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing), a technique for assessing genome-wide chromatin accessibility and DNA methylation.

Differential Methylation

The team identified gene regulatory mechanisms in which cells from responders differed from those of nonresponders, including hypermethylation of genes known to be repressed in embryonic cells and cancer stem cells.

Cells resistant to CAR T had regions of open chromatin that were characteristic of stem-cell proliferation and had patterns similar to those of hematopoietic progenitor and myeloid progenitor cells.

In a press release, senior author Javed Khan, MD, deputy chief of the genetics branch at NCI, noted that prior studies have shown that a switch from lymphoid to myeloid lineage (as seen, for example, in acute myeloid leukemia [AML]) has been shown to be a resistance mechanism to CAR T therapy.

“Interestingly, we saw subpopulations of cells expressing both lymphoid and myeloid markers, indicating that the epigenomes of some nonresponsive leukemias may contain a hybrid population of cells with a hybrid of ALL and AML epigenomes,” Khan said. “Our data suggest that these leukemias, characterized by both lymphoid and myeloid-specific accessible regions, are likely less differentiated than responsive leukemias.”

Cells that did not respond to CAR T therapy also demonstrated decreased expression of genes that code for antigen presentation and processing pathways, indicating a diminished T-cell response.

The study was funded by NIH, the Seattle Children’s Research Institute, Stand Up to Cancer, Strong Against Cancer, Alex’s Lemonade Stand, the St. Baldrick’s Foundation, and the NIH Oxford-Cambridge Scholars Program. Masih, Khan, and Lopez have disclosed no relevant financial relationships.

American Association for Cancer Research (AACR) Annual Meeting 2022: Abstract 3581. Presented April 12, 2022.

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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