The genomic and epigenetic signatures of a subset of pediatric patients with B-cell acute lymphoblastic leukemia (ALL) for which CD19 chimeric antigen receptor (CAR) T-cell (CAR-T) therapy was expected to work revealed new possible mechanisms of resistance to the adoptive cell therapy. The findings were presented at the 2019 American Society of Gene and Cell Therapy (ASGCT) annual meeting, held April 29 to May 2, 2019, in Washington, D.C.1

The subset of patients enrolled in the phase I PLAT-02 trial (ClinicalTrials.gov identifier: NCT02028455) had prognostic markers of response (ie, long-term B-cell aplasia and greater than 15% CD19 positive cells in the bone marrow), yet did not respond. To identify new possible mechanisms of resistance, study researchers performed genomic and epigenetic analyses on specimens derived from 9 patients with CD19-positive B-cell ALL. Four of the patients did not respond to CAR-T and were considered dysfunctional responders, and 5 patients responded to CAR-T and served as controls.

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Using RNA sequencing, study researchers identified upregulated transcription factors among the dysfunctional responders, particularly in the Jund/JUN network. Gene set enrichment analysis revealed enrichment of normal immune signatures among responders. The presence of fusion genes that drive epigenetic remodeling (ie, CREBBP) were found among dysfunctional responders, and dysfunctional responders had more than 10,000 unique open chromatin domains compared with only a few hundred in responders.

The study presenter c, PhD, department of pediatrics, University of Washington School of Medicine, Seattle, concluded the presentation by proposing possible reasons for dysfunctional responses. He offered that perhaps dysfunctional responses are due to rapid tumor escape as a result of selection of a preexisting clone or perhaps all clones looked at are intrinsically resistant due to plasticity.

In light of the finding that responders had an enrichment of normal immune signatures, Dr Orentas said, perhaps CAR-T activity requires a “more normal” marrow in order to support a functional CAR-T response that would fully eradicate the disease.

Reference

  1. Orentas RJ, Masih KE, Gryder BE, et al. Genomic and epigenetic analysis of patient-derived pediatric B cell acute lymphoblastic leukemia (B-ALL) to define new mechanisms of resistance to CD19 CAR-T cell therapy. Presented at: 2019 American Society of Gene and Cell Therapy (ASGCT) Annual Meeting; Washington, D.C.; April 29-May 2, 2019. Abstract 359.