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

Theruvath, Johanna; Sotillo, Elena; Mount, Christopher; Graef, Claus Moritz; Delaidelli, Alberto; Heitzeneder, Sabine; Labanieh, Louai; Dhingra, Shaurya; Leruste, Amaury; Majzner, Robbie G.; Xu, Peng; Mueller, Sabine; Yecies, Derek; Finetti, Martina; Williamson, Daniel; Johann, Pascal; Kool, Marcel; Pfister, Stefan M.; Hasselblatt, Martin; Frühwald, Michael C.; Delattre, Olivier; Surdez, Didier; Bourdeaut, Franck; Puget, Stéphanie; Zaïdi, Sakina; Mitra, Siddhartha; Cheshier, Samuel; Sorensen, Poul H.; Monje, Michelle; Mackall, Crystal L.

doi:10.1038/s41591-020-0821-8

Cited by 191 publications

(177 citation statements)

References 48 publications

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“…While CAR T-cell therapy has shown great promise in the treatment of hematologic diseases, the generation of durable responses against tumor relapse remains an obstacle. We here propose that ICVdelivery of CD19-CAR T cells holds superior potential to treat CNS and systemic lymphoma, which supports the conclusions of two recently published studies that demonstrate that ICV-delivered CAR T cells more effectively control primary and metastatic brain tumors (31,44). In the present study, ICVdelivered CAR T cells potently eradicated both CNS and systemic lymphoma, leading to lymphoma elimination, in conditions where equal or higher doses of IV-delivered CAR T cells did not yield disease elimination (Figure 1-2).…”

Section: Discussionsupporting

confidence: 87%

The Cerebroventricular Environment Modifies CAR T Cells for Potent Activity against Both Central Nervous System and Systemic Lymphoma

Wang

Huynh

Urak

et al. 2021

Cancer Immunology Research

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Lymphomas with central nervous system (CNS) involvement confer a worse prognosis than those without CNS involvement, and patients currently have limited treatment options. T cells genetically engineered with CD19-targeted chimeric antigen receptors (CAR) are effective against B-cell malignancies and show tremendous potential in the treatment of systemic lymphoma. We aimed to leverage this strategy toward a more effective therapy for patients with lymphoma with CNS disease. NOD-scid IL2Rgamma null (NSG) mice with CNS and/or systemic lymphoma were treated with CD19-CAR T cells via intracerebroventricular (ICV) or intravenous (IV) injection. CAR T cells isolated post-treatment were rigorously examined for phenotype, gene expression, and function. We observed that CAR T cells infused ICV, but not IV, completely and durably eradicated both CNS and systemic lymphoma. CAR T cells delivered ICV migrated efficiently to the periphery, homed to systemic tumors, and expanded in vivo, leading to complete elimination of disease and resistance to tumor re-challenge. Mechanistic studies indicated that ICV-delivered CAR T cells are conditioned by exposure to cerebrospinal fluid in the ICV environment for superior anti-lymphoma activity and memory function compared with IV-delivered CAR T cells. Further analysis suggested that manipulating cellular metabolism or pre-activating therapeutic CAR T cells with antigen ex vivo may improve the efficacy of CAR T cells in vivo. Our demonstration that ICV-delivered CD19-CAR T cells had activity against CNS and systemic lymphoma could offer a valuable new strategy for treatment of B-cell malignancies with CNS involvement.

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Section: Discussionsupporting

confidence: 87%

The Cerebroventricular Environment Modifies CAR T Cells for Potent Activity against Both Central Nervous System and Systemic Lymphoma

Wang

Huynh

Urak

et al. 2021

Cancer Immunology Research

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“…As for CAR T cells, CD276 has been evaluated as a potential immunotherapy target for a variety of solid tumor entities in pre‐clinical studies 46 . CD276‐CAR T cell therapies show potent efficacy in preclinical models of a variety of malignancies, including pediatric solid tumors, brain tumors, pancreatic adenocarcinoma, liver cancer, colon cancer, breast cancer, cervical cancer, ovarian cancer, and melanoma 26,45‐48,66,67 . To date, there are only a few clinical trials focusing in CD276 as target which are still in their early stages and there is not one active trial specifically for NB.…”

Section: Discussionmentioning

confidence: 99%

CD276 as a novel CAR NK‐92 therapeutic target for neuroblastoma

et al. 2020

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“…Compared to the intravenous route, B7-H3 CAR T administered intratumorally and intracerebroventricularly showed multiple advantages. i) First, survival benefit was significantly higher; ii) Second, lower numbers of CART cells were required to cure the mice; iii) Third, Inflammatory cytokines such as IFN-g, interleukin-4 (IL-4), IL-10 were not elevated, and; iv) Fourth, tumor penetration was significantly higher (62). Along the same line, Taylor and colleagues demonstrated in group 3 Medulloblastoma that intraventricular administration of EPHA2-targeting CAR T cells showed superior therapeutic effects, allowed penetration to the tumor and CAR T cell persistence due to continuous activation in the tumor site (63).…”

Section: Regional Delivery Of T-cell-based Immunotherapy For Cns Tumorsmentioning

confidence: 99%

Strategies to Enhance the Efficacy of T-Cell Therapy for Central Nervous System Tumors

et al. 2020

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

Cited by 191 publications

References 48 publications

The Cerebroventricular Environment Modifies CAR T Cells for Potent Activity against Both Central Nervous System and Systemic Lymphoma

The Cerebroventricular Environment Modifies CAR T Cells for Potent Activity against Both Central Nervous System and Systemic Lymphoma

CD276 as a novel CAR NK‐92 therapeutic target for neuroblastoma

Strategies to Enhance the Efficacy of T-Cell Therapy for Central Nervous System Tumors

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