CD19-targeting CAR T cell immunotherapy outcomes correlate with genomic modification by vector integration

Area of Science:

• Immunology
• Genetics
• Oncology

Background:

• Chimeric antigen receptor T cells targeting CD19 (CART19) are effective for pediatric acute lymphoblastic leukemia but less so for chronic lymphocytic leukemia (CLL).
• Lentiviral vector integration during CART19 therapy causes insertional mutagenesis, marking cell lineages and potentially influencing therapeutic outcomes.
• Previous findings indicated a link between vector integration within the TET2 gene and CLL remission.

Purpose of the Study:

• To investigate the clonal population structure and therapeutic outcomes in CLL patients treated with CART19 therapy.
• To identify specific gene pathways associated with successful CART19 therapy through analysis of vector integration sites.
• To develop a predictive model for forecasting patient response to CART19 therapy based on integration-site distributions.

Main Methods:

• High-throughput sequencing of vector-integration sites in 39 CLL patients.
• Analysis of genes located at integration sites enriched in responders.
• Development and validation of a multivariate model using integration-site distributions from preinfusion and day 28 samples.

Main Results:

• Genes at integration sites in responders were frequently involved in cell-signaling and chromatin modification pathways, suggesting a role in T cell proliferation.
• A multivariate model based on integration-site distributions accurately forecasted CLL response in discovery and validation cohorts.
• Day 28 samples with integration-site data demonstrated high accuracy in identifying responders to CLL therapy.

Conclusions:

• Insertional mutagenesis at specific genomic locations can modulate T cell proliferation and enhance CART19 efficacy in CLL.
• Integration-site distribution analysis provides a valuable tool for predicting therapeutic outcomes in CART19-treated CLL patients.
• Understanding the impact of insertional mutagenesis on T cell behavior is crucial for optimizing CART19 therapy for CLL.