Clinical cancer research : an official journal of the American Association for Cancer Research · 2013
Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T cells.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Hudecek Michael, Lupo-Stanghellini Maria-Teresa, Kosasih Paula L, Sommermeyer Daniel, Jensen Michael C, Rader Christoph, Riddell Stanley R
Аннотация
PURPOSE: The adoptive transfer of T cells modified to express a chimeric antigen receptor (CAR) comprised of an extracellular single-chain antibody (scFV) fragment specific for a tumor cell surface molecule, and linked to an intracellular signaling module, has activity in advanced malignancies. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a tumor-associated molecule expressed in prevalent B-lymphoid and epithelial cancers and is absent on normal mature B cells and vital tissues, making it a candidate for CAR T-cell therapy.
EXPERIMENTAL DESIGN: We constructed ROR1-CARs from scFVs with different affinities and containing extracellular IgG4-Fc spacer domains of different lengths, and evaluated the ability of T cells expressing each CAR to recognize ROR1(+) hematopoietic and epithelial tumors in vitro, and to eliminate human mantle cell lymphoma (MCL) engrafted into immunodeficient mice.
RESULTS: ROR1-CARs containing a short "Hinge-only" extracellular spacer conferred superior lysis of ROR1(+) tumor cells and induction of T-cell effector functions compared with CARs with long "Hinge-CH2-CH3" spacers. CARs derived from a higher affinity scFV conferred maximum T-cell effector function against primary CLL and ROR1(+) epithelial cancer lines in vitro without inducing activation-induced T-cell death. T cells modified with an optimal ROR1-CAR were equivalently effective as CD19-CAR-modified T cells in mediating regression of JeKo-1 MCL in immunodeficient mice.
CONCLUSIONS: Our results show that customizing spacer design and increasing affinity of ROR1-CARs enhances T-cell effector function and recognition of ROR1(+) tumors. T cells modified with an optimized ROR1-CAR have significant antitumor efficacy in a preclinical model in vivo, suggesting they may be useful to treat ROR1(+) tumors in clinical applications.
EXPERIMENTAL DESIGN: We constructed ROR1-CARs from scFVs with different affinities and containing extracellular IgG4-Fc spacer domains of different lengths, and evaluated the ability of T cells expressing each CAR to recognize ROR1(+) hematopoietic and epithelial tumors in vitro, and to eliminate human mantle cell lymphoma (MCL) engrafted into immunodeficient mice.
RESULTS: ROR1-CARs containing a short "Hinge-only" extracellular spacer conferred superior lysis of ROR1(+) tumor cells and induction of T-cell effector functions compared with CARs with long "Hinge-CH2-CH3" spacers. CARs derived from a higher affinity scFV conferred maximum T-cell effector function against primary CLL and ROR1(+) epithelial cancer lines in vitro without inducing activation-induced T-cell death. T cells modified with an optimal ROR1-CAR were equivalently effective as CD19-CAR-modified T cells in mediating regression of JeKo-1 MCL in immunodeficient mice.
CONCLUSIONS: Our results show that customizing spacer design and increasing affinity of ROR1-CARs enhances T-cell effector function and recognition of ROR1(+) tumors. T cells modified with an optimized ROR1-CAR have significant antitumor efficacy in a preclinical model in vivo, suggesting they may be useful to treat ROR1(+) tumors in clinical applications.