Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors

被引：216

作者：

Theruvath, Johanna ^{[1
]}

Sotillo, Elena ^{[1
]}

Mount, Christopher W. ^{[2
]}

Graef, Claus Moritz ^{[1
]}

Delaidelli, Alberto ^{[3
]}

Heitzeneder, Sabine ^{[1
]}

Labanieh, Louai ^{[1
,4
]}

Dhingra, Shaurya ^{[1
]}

Leruste, Amaury ^{[1
]}

Majzner, Robbie G. ^{[1
,5
]}

Xu, Peng ^{[1
]}

Mueller, Sabine ^{[6
,7
,8
,19
]}

Yecies, Derek W. ^{[9
]}

Finetti, Martina A. ^{[10
]}

Williamson, Daniel ^{[10
]}

Johann, Pascal D. ^{[1
,11
,12
,13
]}

Kool, Marcel ^{[11
,12
,13
]}

Pfister, Stefan ^{[11
,12
,13
,14
]}

Hasselblatt, Martin ^{[15
]}

Fruehwald, Michael C. ^{[16
,17
]}

Delattre, Olivier ^{[18
,19
]}

Surdez, Didier ^{[18
,19
]}

Bourdeaut, Franck ^{[1
,18
,19
]}

Puget, Stephanie ^{[20
]}

Zaidi, Sakina ^{[18
,19
]}

Mitra, Siddhartha S. ^{[21
]}

Cheshier, Samuel ^{[22
,23
]}

Sorensen, Poul H. ^{[3
]}

Monje, Michelle ^{[1
,2
,5
,9
,24
,25
]}

Mackall, Crystal L. ^{[1
,5
,26
]}

机构：

[1] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA

[2] Stanford Univ, Dept Neurol, Sch Med, Stanford, CA 94305 USA

[3] British Columbia Canc Res Ctr, Dept Mol Oncol, Vancouver, BC, Canada

[4] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA

[5] Stanford Univ, Stanford Canc Inst, Sch Med, Stanford, CA 94305 USA

[6] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA

[7] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA

[8] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA

[9] Stanford Univ, Dept Neurosurg, Sch Med, Stanford, CA 94305 USA

[10] Newcastle Univ, Northern Inst Canc Res, Wolfson Childhood Canc Res Ctr, Newcastle Upon Tyne, Tyne & Wear, England

[11] Hopp Childrens Canc Ctr Heidelberg, Heidelberg, Germany

[12] German Canc Res Ctr, Div Pediat Neurooncol, Heidelberg, Germany

[13] German Canc Consortium, Heidelberg, Germany

[14] Heidelberg Univ Hosp, Dept Pediat Hematol & Oncol, Heidelberg, Germany

[15] Munster Univ Hosp, Inst Neuropathol, Munster, Germany

[16] Univ Childrens Hosp Augsburg, Swabian Childrens Canc Ctr, Augsburg, Germany

[17] EU RHAB Registry Ctr, Augsburg, Germany

[18] Paris Sci Lettres Res Univ, INSERM, U830, Paris, France

[19] Paris Sci Lettres Res Univ, SIREDO Care Innovat & Res Children Adolescents &, Inst Curie, Paris, France

[20] Paris Univ, Necker Enfants Malad Hosp, AP HP, Dept Neurosurg, Paris, France

[21] Univ Colorado Anschutz Med Campus, Pediat, Aurora, CO USA

[22] Univ Utah, Primary Childrens Hosp, Dept Neurosurg, Div Pediat Neurosurg, Salt Lake City, UT USA

[23] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA

[24] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA

[25] Stanford Univ, Stanford Inst Stem Cell & Regenerat Med, Sch Med, Stanford, CA 94305 USA

[26] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA

来源：

NATURE MEDICINE | 2020年 / 26卷 / 05期

基金：

欧盟地平线“2020”; 美国国家卫生研究院;

关键词：

ANTIGEN; CANCER; B7-H3; EXPRESSION; EFFICACY; SURVIVAL; THERAPY; ABSENCE; TARGETS; HER2;

D O I：

10.1038/s41591-020-0821-8

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months(1,2). We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. (3,4)), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT(5,6), B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies. CAR T cells administered intracerebroventricularly or intratumorally exhibit more rapid kinetics, reduced systemic toxicity and greater therapeutic potency as compared to intravenously delivered CAR T cells in atypical teratoid/rhabdoid tumor xenograft mouse models.

引用

页码：712 / +

页数：22

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