CAR-T细胞介导的神经母细胞瘤双特异性先天免疫细胞接合剂的递送-动脉网

CAR T-cell-mediated delivery of bispecific innate immune cell engagers for neuroblastoma

Nature 等信源发布 2024-08-21 08:40

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AbstractNovel chimeric antigen receptor (CAR) T-cell approaches are needed to improve therapeutic efficacy in solid tumors. High-risk neuroblastoma is an aggressive pediatric solid tumor that expresses cell-surface GPC2 and GD2 with a tumor microenvironment infiltrated by CD16a-expressing innate immune cells.

摘要需要新的嵌合抗原受体（CAR）T细胞方法来提高实体瘤的治疗效果。高危神经母细胞瘤是一种侵袭性儿科实体瘤，表达细胞表面GPC2和GD2，肿瘤微环境被表达CD16a的先天免疫细胞浸润。

Here we engineer T-cells to express a GPC2-directed CAR and simultaneously secrete a bispecific innate immune cell engager (BiCE) targeting both GD2 and CD16a. In vitro, GPC2.CAR-GD2.BiCE T-cells induce GPC2-dependent cytotoxicity and secrete GD2.BiCE that promotes GD2-dependent activation of antitumor innate immunity.

在这里，我们设计T细胞表达GPC2定向的CAR，同时分泌靶向GD2和CD16a的双特异性先天免疫细胞参与者（BiCE）。在体外，GPC2.CAR-GD2.BiCE T细胞诱导GPC2依赖性细胞毒性并分泌GD2.BiCE，其促进抗肿瘤先天免疫的GD2依赖性激活。

In vivo, GPC2.CAR-GD2.BiCE T-cells locally deliver GD2.BiCE and increase intratumor retention of NK-cells. In mice bearing neuroblastoma patient-derived xenografts and reconstituted with human CD16a-expressing immune cells, GD2.BiCEs enhance GPC2.CAR antitumor efficacy. A CAR.BiCE strategy should be considered for tumor histologies where antigen escape limits CAR efficacy, especially for solid tumors like neuroblastoma that are infiltrated by innate immune cells..

在体内，GPC2.CAR-GD2.BiCE T细胞局部递送GD2.BiCE并增加NK细胞的肿瘤内保留。在携带神经母细胞瘤患者来源的异种移植物并用表达人CD16a的免疫细胞重建的小鼠中，GD2.BICE增强了GPC2.CAR的抗肿瘤功效。一辆汽车。对于抗原逃逸限制CAR疗效的肿瘤组织学，应考虑BiCE策略，特别是对于先天免疫细胞浸润的神经母细胞瘤等实体瘤。。

IntroductionT-cells can be directed to tumor cells by expressing a chimeric antigen receptor (CAR)1. CAR T-cell therapies have shown unprecedented clinical responses against hematological malignancies2, but their efficacy against solid tumors remains limited. Solid tumors can escape CAR therapeutic pressure by inducing antigen downregulation, via inherent antigen heterogeneity or through the immunosuppressive tumor microenvironment (TME)3.

引言通过表达嵌合抗原受体（CAR）1，可以将T细胞定向到肿瘤细胞。CAR T细胞疗法对血液系统恶性肿瘤显示出前所未有的临床反应2，但其对实体瘤的疗效仍然有限。实体瘤可以通过诱导抗原下调，通过固有的抗原异质性或通过免疫抑制性肿瘤微环境（TME）3来逃避CAR治疗压力。

To circumvent these barriers to sustained efficacy, next-generation CARs have been engineered to modify T-cell intracellular signaling to enable greater recognition of antigen-low tumors and maintain persistence4, target more than one tumor cell surface antigen simultaneously5 or locally deliver additional therapeutic agents to remodel the TME6,7,8.

为了克服这些持续疗效的障碍，下一代CAR已被设计用于修饰T细胞细胞内信号传导，以更好地识别抗原低的肿瘤并维持持久性4，同时靶向多于一种肿瘤细胞表面抗原5或局部递送额外的治疗剂以重塑TME6,7,8。

Since innate immune cell activation is required for optimal T-cell performance9,10, CAR T-cell-mediated delivery of cytokines11, nanobodies6 or bacterial factors12 that boost innate immune cell sustenance within the TME are especially attractive. Other therapeutic strategies that exploit innate immunity include bispecific engagers built from antibody fragments that target both tumor-associated antigens and activate receptors on natural killer (NK) cells or macrophages13, but their therapeutic combination with CAR T-cells has not been explored.High-risk neuroblastoma is a pediatric tumor arising from neural crest progenitors that has a dismal prognosis despite intense multimodal cytotoxic therapies14.

由于先天性免疫细胞活化是最佳T细胞性能所必需的[9,10]，因此CAR T细胞介导的细胞因子11，纳米体6或细菌因子12在TME内促进先天性免疫细胞的维持尤其有吸引力。利用先天免疫的其他治疗策略包括由靶向肿瘤相关抗原并激活自然杀伤（NK）细胞或巨噬细胞上受体的抗体片段构建的双特异性参与者13，但尚未探索它们与CAR T细胞的治疗组合。高风险神经母细胞瘤是由神经c祖细胞产生的儿科肿瘤，尽管有强烈的多模式细胞毒性治疗，但预后不佳14。

High-risk neuroblastoma tumors are in part characterized by a T-cell-excluded TME, but alternatively harbor a substantial infiltration of innate immune cells including macrophages, NK-cells and other myeloid cell populations15. Immunotherapy with monoclonal antibodies (mAb) against the disialo.

高风险神经母细胞瘤肿瘤的部分特征是T细胞排除的TME，但也有大量先天免疫细胞浸润，包括巨噬细胞，NK细胞和其他骨髓细胞群15。。

Data availability

数据可用性

High-risk neuroblastoma TARGET gene expression data were downloaded from (https://treehousegenomics.soe.ucsc.edu/public-data), whereas human normal tissue gene expression data were downloaded from the GTEx portal (https://gtexportal.org/home/datasets). RDS files for neuroblastoma single-cell RNA-sequencing data were downloaded from (https://www.neuroblastomacellatlas.org).

高危神经母细胞瘤靶基因表达数据下载自(https://treehousegenomics.soe.ucsc.edu/public-data)，而人类正常组织基因表达数据是从GTEx门户网站下载的(https://gtexportal.org/home/datasets)。神经母细胞瘤单细胞RNA测序数据的RDS文件下载自(https://www.neuroblastomacellatlas.org)。

All other data are available in the Article, Supplementary Information or the Source Data file that is provided with this paper. Source data are provided with this paper..

所有其他数据均可在本文提供的文章，补充信息或源数据文件中找到。本文提供了源数据。。

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Download referencesAcknowledgementsKristopher R. Bosse is a Damon Runyon Physician-Scientist supported (in part) by the Damon Runyon Cancer Research Foundation (PST-07-16). This work was supported in part by a St. Baldrick’s-Stand Up to Cancer Dream Team Translational Research Grant (SU2C-AACR-DT-27-17).

下载参考文献致谢Kristopher R.Bosse是Damon Runyon癌症研究基金会（PST-07-16）支持（部分）的Damon Runyon医师科学家。这项工作部分得到了圣波尔德里克抗癌梦之队转化研究基金（SU2C-AACR-DT-27-17）的支持。

Stand Up to Cancer is a division of the Entertainment Industry Foundation. Research Grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. This work was also supported by the Alex’s Lemonade Stand Foundation (G.P.-P, A.J.W. and K.R.B.), by NCI K08 CA230223 (K.R.B.) and CA266914 (A.J.W.), NCI R37 CA282041 (K.R.B.), NCI U54 CA232568 (K.R.B.), a Children’s Hospital of Philadelphia Cell and Gene Therapy Collaborative Seed Grant (K.R.B.), the EVAN Foundation (K.R.B.), Solving Kids’ Cancer (K.R.B.), Fishin’ For The Cure (K.R.B.), Pierce Phillips Charity (K.R.B.), Catherine Elizabeth Blair Memorial Foundation (K.R.B.) and the Ronan Thompson Foundation (K.R.B.).

勇敢面对癌症是娱乐业基金会的一个部门。研究资助由SU2C的科学合作伙伴美国癌症研究协会管理。这项工作也得到了亚历克斯柠檬水站基金会（G.P.-P，A.J.W.和K.R.B.）的支持，NCI K08 CA230223（K.R.B.）和CA266914（A.J.W.），NCI R37 CA282041（K.R.B.），NCI U54 CA232568（K.R.B.），费城儿童医院细胞和基因治疗合作种子基金会（K.R.B.），埃文基金会（K.R.B.），解决儿童癌症（K.R.B.），钓鱼治疗（K.R.B.）的支持。B.）、皮尔斯·菲利普斯慈善机构（K.R.B.）、凯瑟琳·伊丽莎白·布莱尔纪念基金会（K.R.B.）和罗南·汤普森基金会（K.R.B.）。

We thank the DNA sequencing and Human Immunology core facilities at the University of Pennsylvania for their work on plasmid verification and human immune cell isolation, respectively. We also would like to thank the Pathology and Small Animal Imaging facility cores at the Children’s Hospital of Philadelphia.

我们感谢宾夕法尼亚大学的DNA测序和人类免疫学核心设施分别在质粒验证和人类免疫细胞分离方面的工作。我们还要感谢费城儿童医院的病理学和小动物成像设施核心。

We would like to acknowledge the Center for Childhood Cancer Research (CCCR) Biorepository and Registry for providing the bone marrow specimens from neuroblastoma patients and Drs. Amy Erbe and Paul Sondel for providing the GD2 synthase vector.Author informationAuthor notesLaura Garcia-GeriquePresent address: Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USAMark YarmarkovichPrese.

我们要感谢儿童癌症研究中心（CCCR）生物储存和登记处提供神经母细胞瘤患者的骨髓标本，以及Amy Erbe和Paul Sondel博士提供GD2合酶载体。作者信息作者notesLaura Garcia GeriquePresent地址：宾夕法尼亚大学佩雷尔曼医学院细胞免疫治疗中心，宾夕法尼亚州费城，19104，USAMark YarmarkovichPrese。

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PubMed Google ScholarContributionsConceptualization: G.P.-P., K.R.B. Methodology: G.P.-P., M.G.H, T.H., W.L., K.R.B. Investigation: G.P.-P., B.M., A.M.G., J.H., L.G.-G., S.M., S.L., P.M.S., M.Y., W.L., K.R.B. Formal analysis: G.P.-P., P.M., R.S., F.A., K.R.B. Visualization: G.P.-P., K.R.B.

PubMed谷歌学术贡献概念化：G.P.-P.，K.R.B.方法论：G.P.-P.，M.G.H，T.H.，W.L.，K.R.B.调查：G.P.-P.，B.M.，A.M.G.，J.H.，L.G.-G.，S.M.，S.L.，P.M.S.，M.Y.，W.L.，K.R.B.形式分析：G.P.-P.，P.M.，R.S.，F.A.，K.R.B.可视化：G.P.-P.，K.R.B。

Funding acquisition: G.P.-P., K.R.B. Resources: D.M., M.T., L.G-d-G., A.J.W., T.S., K.M.B., D.S.D., W.L., K.R.B. Supervision: G.P.-P., K.R.B. Writing – original draft: G.P.-P., K.R.B. Writing – review & editing: All authors.Corresponding authorCorrespondence to.

资金获取：G.P.-P.，K.R.B.资源：D.M.，M.T.，L.G-D-G.，A.J.W.，T.S.，K.M.B.，D.S.D.，W.L.，K.R.B.监督：G.P.-P.，K.R.B.写作-原稿：G.P.-P.，K.R.B.写作-评论和编辑：所有作者。对应作者对应。

Kristopher R. Bosse.Ethics declarations

克里斯托弗·博塞。道德宣言

Competing interests

相互竞争的利益

G.P.-P. and K.R.B. report having a pending patent directly related to this work entitled Dual targeting of pediatric malignancies through CAR T cells secreting Bispecific Innate Immune Cell Engagers (BICEs) (International Patent Application No. PCT/US2022/080935). M.Y., D.S.D., W.L. and K.R.B. hold patents for the discovery and development of other immunotherapies for cancer, including patents related to GPC2 and CD16a-directed immunotherapies.

G、。M、 Y.，D.S.D.，W.L.和K.R.B.拥有发现和开发其他癌症免疫疗法的专利，包括与GPC2和CD16a定向免疫疗法相关的专利。

M.Y. is a co-founder of Hula Therapeutics. K.R.B. receives royalties and research funding from Tmunity/Kite Pharma and ConjugateBio for research on GPC2-directed immunotherapies. K.R.B. is on the ConjugateBio Scientific Advisory Board. K.M.B. has received research funding from Syndax. The remaining authors declare no competing interests..

M、 Y.是Hula Therapeutics的联合创始人。K、 R.B.从Tmunity/Kite Pharma和ConjugateBio获得版税和研究资金，用于GPC2定向免疫疗法的研究。K、 R.B.是ConjugateBio科学咨询委员会的成员。K、 M.B.已获得Syndax的研究资助。其余作者声明没有利益冲突。。

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Nature Communications thanks John Anderson, Rosa Nguyen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

Nature Communications感谢约翰·安德森（JohnAnderson）、罗莎·阮（RosaNguyen）和另一位匿名审稿人对这项工作的同行评审所做的贡献。同行评审文件可用。

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Reprints and permissionsAbout this articleCite this articlePascual-Pasto, G., McIntyre, B., Hines, M.G. et al. CAR T-cell-mediated delivery of bispecific innate immune cell engagers for neuroblastoma.

转载和许可本文引用本文Pascual-Pasto，G.，McIntyre，B.，Hines，M.G。等人CAR T细胞介导的双特异性先天免疫细胞接受者对神经母细胞瘤的递送。

Nat Commun 15, 7141 (2024). https://doi.org/10.1038/s41467-024-51337-2Download citationReceived: 03 October 2023Accepted: 06 August 2024Published: 21 August 2024DOI: https://doi.org/10.1038/s41467-024-51337-2Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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