10.6084/M9.FIGSHARE.C.6289234.V1
Lipei Shao
Lipei
Shao
National Institutes of Health Clinical Center
Rongye Shi
Rongye
Shi
National Institutes of Health Clinical Center
Yingdong Zhao
Yingdong
Zhao
National Cancer Institute
Hui Liu
Hui
Liu
National Institutes of Health Clinical Center
Alexander Lu
Alexander
Lu
National Institutes of Health Clinical Center
Jinxia Ma
Jinxia
Ma
National Institutes of Health Clinical Center
Yihua Cai
Yihua
Cai
National Institutes of Health Clinical Center
Tatyana Fuksenko
Tatyana
Fuksenko
National Institutes of Health Clinical Center
Alejandra Pelayo
Alejandra
Pelayo
National Institutes of Health Clinical Center
Nirali N. Shah
Nirali N.
Shah
Center for Cancer Research
James N. Kochenderfer
James N.
Kochenderfer
Center for Cancer Research
Scott M. Norberg
Scott M.
Norberg
National Cancer Institute
Christian Hinrichs
Christian
Hinrichs
National Cancer Institute
Steven L. Highfill
Steven L.
Highfill
National Institutes of Health Clinical Center
Robert P Somerville
Robert P
Somerville
National Institutes of Health Clinical Center
Sandhya R. Panch
Sandhya R.
Panch
National Institutes of Health Clinical Center
Ping Jin
Ping
Jin
National Institutes of Health Clinical Center
David F. Stroncek
David F.
Stroncek
National Institutes of Health Clinical Center
Genome-wide profiling of retroviral DNA integration and its effect on clinical pre-infusion CAR T-cell products
Abstract Background Clinical CAR T-cell therapy using integrating vector systems represents a promising approach for the treatment of hematological malignancies. Lentiviral and γ-retroviral vectors are the most commonly used vectors in the manufacturing process. However, the integration pattern of these viral vectors and subsequent effect on CAR T-cell products is still unclear. Methods We used a modified viral integration sites analysis (VISA) pipeline to evaluate viral integration events around the whole genome in pre-infusion CAR T-cell products. We compared the differences of integration pattern between lentiviral and γ-retroviral products. We also explored whether the integration sites correlated with clinical outcomes. Results We found that γ-retroviral vectors were more likely to insert than lentiviral vectors into promoter, untranslated, and exon regions, while lentiviral vector integration sites were more likely to occur in intron and intergenic regions. Some integration events affected gene expression at the transcriptional and post-transcriptional level. Moreover, γ-retroviral vectors showed a stronger impact on the host transcriptome. Analysis of individuals with different clinical outcomes revealed genes with differential enrichment of integration events. These genes may affect biological functions by interrupting amino acid sequences and generating abnormal proteins, instead of by affecting mRNA expression. These results suggest that vector integration is associated with CAR T-cell efficacy and clinical responses. Conclusion We found differences in integration patterns, insertion hotspots and effects on gene expression vary between lentiviral and γ-retroviral vectors used in CAR T-cell products and established a foundation upon which we can conduct further analyses.
Genetics
figshare
2022
2022-11-09
2022-11-09
Collection
10.6084/m9.figshare.c.6289234
CC BY 4.0