Certain genetic patterns may predict response to CAR-T for acute lymphoblastic leukemia
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Younger patients with acute lymphoblastic leukemia who do not respond to CD19-directed chimeric antigen receptor T-cell therapy exhibit certain gene regulation patterns that may be associated with treatment resistance, study results show.
Data from multi-omic analysis conducted by researchers at NCI and presented at American Association for Cancer Research Annual Meeting suggest there are potential clinical biomarkers that can be used to determine which patients may not respond to CD19-directed CAR-T cell therapy prior to treatment.
Background
B-cell ALL is the most common cancer among children but is highly curable, according to Katherine E. Masih, an MD/PhD student in the NIH Oxford-Cambridge Scholars Program.
Despite the high cure rate, patients who experience disease relapse have far worse outcomes, with a survival rate of approximately 40%.
“CD19 CAR T cells have completely changed the treatment landscape for children with this disease, leading to remissions in approximately 80% of patients with relapsed or refractory B-cell ALL,” she said during a press conference. “Unfortunately, the durable response rate is closer to 50%, which highlights the need for pretreatment biomarkers as a means to prioritize treatment with CD19-directed CAR-T for patients who do respond to therapy.”
Methods
Masih and colleagues obtained pretreatment bone marrow samples from 14 patients enrolled in the phase 1/phase 2 PLAT-02 trial being conducted at Seattle Children’s Hospital. The investigators wanted to identify genomic characteristics of patients who do not respond to CD19-directed CAR T-cell therapy.
Seven samples came from seven patients who experienced a complete response to therapy after CD19-directed CAR-T compared with seven patients who did not maintain minimal residual disease negativity as of 63 days after infusion.
The investigators used a variety of sequencing techniques to identify any genetic variants between patients who were resistant to CD19-directed CAR T-cell therapy and those who responded to treatment.
Key findings
The investigators found a distinguishing DNA methylation pattern in samples from patients who were primary nonresponders to CAR T-cell therapy that was associated with a stem cell-like phenotype. These hypermethylated regions are detectable prior to therapy, according to Masih.
DNA accessibility profiles of the leukemia showed regions of open chromatin characteristic of CAR T-cell-resistant leukemia were associated with stem cell proliferation (P < .0001) and “resembled patterns found in hematopoietic progenitor cells, including hematopoietic stem cells (P = .037) and progenitors of myeloid cells (P = .047),” according to the investigators.
The researchers also discovered decreased expression of genes related to antigen presentation and processing in leukemia cells that did not respond to CD19-directed CAR-T (P = .0001).
Clinical implications
“A stem cell epigenome with multilineage potential is a novel marker of primary nonresponse to CD19-directed CAR-T in younger patients with ALL,” Masih said. “[This epigenome] can be detected prior to therapy and serves as a potential biomarker for response to therapy.”
The identification of a reliable biomarker could improve patient selection and determine eligibility for CD19-directed CAR T-cell therapy in the future, she added.
“This could lead to the prioritization of less toxic, targeted therapy and improve patient outcomes,” Masih noted.
Perspective
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Jae Park, MD
There is a pressing need to improve our understanding of potential mechanisms of resistance to CAR T-cell immunotherapy. If we can identify who is most likely to respond before treatment, then we can better select the patients who will most likely benefit before embarking on cell collection, manufacturing and treatment and spare patients from unnecessary toxicities.
This study is one such attempt. It uses comprehensive genetic profiling of tumor samples and reports that leukemia cells with more stem cell-like features are less likely to respond to CD19-targeted CAR T-cell therapy. However, it is important to recognize that this finding may not be generalizable across all CAR T-cell therapy or ALL.
First, this was tested in pediatric ALL patients, who tend to have different genetic phenotypes compared with adults, so it may not be applicable to adults with ALL. Second, the study only tested one CAR-T product, and given the differences in cellular kinetics and potency/persistence, the finding may not be generalizable to other CD19-directed CAR-T products for both pediatric and adult ALL.
Although the findings are certainly very intriguing, why the leukemia cells with stem cell-like features do not respond to CAR T cells (ie, actual resistance mechanism) remains unclear. Furthermore, it would be important to validate the signatures in larger cohorts to see whether this finding is limited to this particular study set vs. being applicable to other CAR-T products for this disease. Nonetheless, the study represents an important step forward to improve our understanding of resistance mechanisms that, hopefully, will lead to better resource utilization and more effective cell therapies for our patients with cancer.
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Masih KE, et al. Abstract 3581. Presented at: American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans.
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