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

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 -