| Literature DB >> 32341580 |
Laura K Donovan1,2, Alberto Delaidelli3, Sujith K Joseph4,5, Kevin Bielamowicz4,5, Kristen Fousek4,5, Borja L Holgado1,2, Alex Manno1,2, Dilakshan Srikanthan1,2,6, Ahmed Z Gad4,5, Randy Van Ommeren1,2,6, David Przelicki1,2,6, Cory Richman1,2,7, Vijay Ramaswamy1,8, Craig Daniels1,2, Jonelle G Pallota1,2, Tajana Douglas1,2, Alyssa C M Joynt1,2, Joonas Haapasalo1,2, Carolina Nor1,2, Maria C Vladoiu1,2,6, Claudia M Kuzan-Fischer1,2, Livia Garzia9, Stephen C Mack10, Srinidhi Varadharajan10, Matthew L Baker5, Liam Hendrikse1,2,7, Michelle Ly1,2,6, Kaitlin Kharas1,2,6, Polina Balin1,2,6, Xiaochong Wu1,2, Lei Qin1,2, Ning Huang1,2, Ana Guerreiro Stucklin1,2, A Sorana Morrissy11,12, Florence M G Cavalli1,2, Betty Luu1,2, Raul Suarez1,2, Pasqualino De Antonellis1,2, Antony Michealraj1,2, Avesta Rastan1,2, Meenakshi Hegde4,5, Martin Komosa1,2, Olga Sirbu1,2,7, Sachin A Kumar1,2, Zied Abdullaev13, Claudia C Faria14, Stephen Yip15, Juliette Hukin16, Uri Tabori1,2, Cynthia Hawkins1,2, Ken Aldape13, Mads Daugaard17,18, John M Maris19,20,21, Poul H Sorensen3, Nabil Ahmed22,23, Michael D Taylor24,25,26,27.
Abstract
Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.Entities:
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Year: 2020 PMID： 32341580 PMCID： PMC8815773 DOI： 10.1038/s41591-020-0827-2
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 53.440