AML-1276: CRISPR-Cas9 Therapies in Hematologic Malignancies: A Meta-Analysis of Clinical Outcomes, Safety, and Translational Implications

Document Type

Conference Proceeding

Publication Date

9-1-2025

Publication Title

Clin Lymphoma Myeloma Leuk

Abstract

CRISPR-based gene editing has introduced transformative possibilities in hematologic oncology, offering precise and durable immunologic interventions. With increasing adoption in early-phase trials, an integrated understanding of its efficacy and safety is essential. Objective: To evaluate the efficacy, safety, and translational potential of CRISPR-Cas9-based therapies in hematologic malignancies through a structured meta-analysis of early-phase clinical trials. Design: Systematic review and meta-analysis of CRISPR-based hematologic cancer trials published between 2019 and 2024. Random-effects modeling was used due to inter-trial heterogeneity. Setting: Academic hospitals and early-phase clinical centers conducting gene-modified cellular therapy trials. Patients or Other Participants: Nine clinical trials encompassing 80 patients with relapsed or refractory hematologic malignancies, including Tcell acute lymphoblastic leukemia (T-ALL), aggressive B-cell lymphomas, and multiple myeloma. Inclusion criteria varied by trial; most patients had exhausted standard therapies. Interventions: All studies employed ex vivo CRISPR editing of immune cells. Interventions included TRAC- and PD-1-knockout chimeric antigen receptor (CAR) T cells, universal CD7-targeted base-edited T cells, and suicide-gene modified donor lymphocytes. Products were administered as single infusions following lymphodepletion. Main Outcome Measures: Overall response rate (ORR), complete response (CR) rate, incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), and detection of off-target edits. Results: The pooled ORR was 62.3% (95% CI, 50.1%–73.2%), with a CR rate of 34.6%. Base-edited CAR7 T cells achieved CR in five of nine pediatric T-ALL patients. CRS occurred in 48% of patients (mostly grade 1–2) and ICANS in ∼17%, with no grade ≥3 events. No treatment-related deaths or clinically significant off-target events were reported. Deep sequencing confirmed primarily on-target edits with rare, non-propagating chromosomal changes. Follow-up ranged from 6 to 12 months. Conclusions: CRISPR-Cas9-based therapies exhibit promising antitumor activity and a manageable safety profile in hematologic cancers. These findings support the clinical viability of gene-edited cellular therapy, especially in relapsed settings. However, larger trials and long-term data are essential to validate the durability, genomic stability, and scalability of these platforms.

Volume

25

First Page

S497

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