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  • Title: Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma.
    Author: Donovan LK, Delaidelli A, Joseph SK, Bielamowicz K, Fousek K, Holgado BL, Manno A, Srikanthan D, Gad AZ, Van Ommeren R, Przelicki D, Richman C, Ramaswamy V, Daniels C, Pallota JG, Douglas T, Joynt ACM, Haapasalo J, Nor C, Vladoiu MC, Kuzan-Fischer CM, Garzia L, Mack SC, Varadharajan S, Baker ML, Hendrikse L, Ly M, Kharas K, Balin P, Wu X, Qin L, Huang N, Stucklin AG, Morrissy AS, Cavalli FMG, Luu B, Suarez R, De Antonellis P, Michealraj A, Rastan A, Hegde M, Komosa M, Sirbu O, Kumar SA, Abdullaev Z, Faria CC, Yip S, Hukin J, Tabori U, Hawkins C, Aldape K, Daugaard M, Maris JM, Sorensen PH, Ahmed N, Taylor MD.
    Journal: Nat Med; 2020 May; 26(5):720-731. PubMed ID: 32341580.
    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.
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