Combining a CD20 chimeric antigen receptor and an inducible caspase 9 suicide switch to improve the efficacy and safety of T cell adoptive immunotherapy for lymphoma
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Combining a CD20 chimeric antigen receptor and an inducible caspase 9 suicide switch to improve the efficacy and safety of T cell adoptive immunotherapy for lymphoma. / Budde, Lihua E; Berger, Carolina; Lin, Yukang; Wang, Jinjuan; Lin, Xubin; Frayo, Shani E; Brouns, Shaunda A; Spencer, David M; Till, Brian G; Jensen, Michael C; Riddell, Stanley R; Press, Oliver W.
In: PLOS ONE, Vol. 8, No. 12, 2013, p. e82742.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Combining a CD20 chimeric antigen receptor and an inducible caspase 9 suicide switch to improve the efficacy and safety of T cell adoptive immunotherapy for lymphoma
AU - Budde, Lihua E
AU - Berger, Carolina
AU - Lin, Yukang
AU - Wang, Jinjuan
AU - Lin, Xubin
AU - Frayo, Shani E
AU - Brouns, Shaunda A
AU - Spencer, David M
AU - Till, Brian G
AU - Jensen, Michael C
AU - Riddell, Stanley R
AU - Press, Oliver W
PY - 2013
Y1 - 2013
N2 - Modification of T cells with chimeric antigen receptors (CAR) has emerged as a promising treatment modality for human malignancies. Integration of co-stimulatory domains into CARs can augment the activation and function of genetically targeted T cells against tumors. However, the potential for insertional mutagenesis and toxicities due to the infused cells have made development of safe methods for removing transferred cells an important consideration. We have genetically modified human T cells with a lentiviral vector to express a CD20-CAR containing both CD28 and CD137 co-stimulatory domains, a "suicide gene" relying on inducible activation of caspase 9 (iC9), and a truncated CD19 selectable marker. Rapid expansion (2000 fold) of the transduced T cells was achieved in 28 days after stimulation with artificial antigen presenting cells. Transduced T cells exhibited effective CD20-specific cytotoxic activity in vitro and in a mouse xenograft tumor model. Activation of the iC9 suicide switch resulted in efficient removal of transduced T cells both in vitro and in vivo. Our work demonstrates the feasibility and promise of this approach for treating CD20(+) malignancies in a safe and more efficient manner. A phase I clinical trial using this approach in patients with relapsed indolent B-NHL is planned.
AB - Modification of T cells with chimeric antigen receptors (CAR) has emerged as a promising treatment modality for human malignancies. Integration of co-stimulatory domains into CARs can augment the activation and function of genetically targeted T cells against tumors. However, the potential for insertional mutagenesis and toxicities due to the infused cells have made development of safe methods for removing transferred cells an important consideration. We have genetically modified human T cells with a lentiviral vector to express a CD20-CAR containing both CD28 and CD137 co-stimulatory domains, a "suicide gene" relying on inducible activation of caspase 9 (iC9), and a truncated CD19 selectable marker. Rapid expansion (2000 fold) of the transduced T cells was achieved in 28 days after stimulation with artificial antigen presenting cells. Transduced T cells exhibited effective CD20-specific cytotoxic activity in vitro and in a mouse xenograft tumor model. Activation of the iC9 suicide switch resulted in efficient removal of transduced T cells both in vitro and in vivo. Our work demonstrates the feasibility and promise of this approach for treating CD20(+) malignancies in a safe and more efficient manner. A phase I clinical trial using this approach in patients with relapsed indolent B-NHL is planned.
KW - Animals
KW - Antigens, CD20/genetics
KW - Caspase 9/genetics
KW - Cells, Cultured
KW - Genes, Transgenic, Suicide
KW - Humans
KW - Immunotherapy, Adoptive/methods
KW - Jurkat Cells
KW - Lymphoma/genetics
KW - Mice
KW - Mice, Inbred NOD
KW - Mice, Knockout
KW - Mice, SCID
KW - NIH 3T3 Cells
KW - Receptors, Antigen, T-Cell/genetics
KW - Recombinant Fusion Proteins/genetics
KW - T-Lymphocytes/metabolism
KW - Treatment Outcome
KW - Xenograft Model Antitumor Assays
U2 - 10.1371/journal.pone.0082742
DO - 10.1371/journal.pone.0082742
M3 - SCORING: Journal article
C2 - 24358223
VL - 8
SP - e82742
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 12
ER -