Journal
EMBO MOLECULAR MEDICINE
Volume 8, Issue 7, Pages 702-711Publisher
WILEY
DOI: 10.15252/emmm.201505869
Keywords
CAR T cells; episomal cell engineering; non-integrating lentivirus (NILV); scaffold/matrix attachment region (S/MAR) element; self-replicating DNA
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Funding
- Swedish Children Cancer Foundation
- Swedish Cancer Society
- Swedish Research Council
- Gunnar Nilsson's Cancer Foundation
- Medical Faculty of Uppsala University
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Chimeric antigen receptor (CAR) T-cell therapy is a new successful treatment for refractory B-cell leukemia. Successful therapeutic outcome depends on long-term expression of CAR transgene in T cells, which is achieved by delivering transgene using integrating gamma retrovirus (RV) or lentivirus (LV). However, uncontrolled RV/LV integration in host cell genomes has the potential risk of causing insertional mutagenesis. Herein, we describe a novel episomal long-term cell engineering method using non-integrating lentiviral (NILV) vector containing a scaffold/matrix attachment region (S/MAR) element, for either expression of transgenes or silencing of target genes. The insertional events of this vector into the genome of host cells are below detection level. CD19 CAR T cells engineered with a NILV-S/MAR vector have similar levels of CAR expression as T cells engineered with an integrating LV vector, even after numerous rounds of cell division. NILV-S/MAR-engineered CD19 CAR T cells exhibited similar cytotoxic capacity upon CD19+ target cell recognition as LV-engineered T cells and are as effective in controlling tumor growth in vivo. We propose that NILV-S/MAR vectors are superior to current options as they enable long-term transgene expression without the risk of insertional mutagenesis and genotoxicity.
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