Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma
Authors: Xiaochong Wu
Stephen Yip
Ken Aldape
Carolina Nor
Martin Komosa
Lei Qin
Jonelle G Pallota
Betty Luu
Joonas Haapasalo
Raul Suarez
Sujith K Joseph
David Przelicki
Maria C Vladoiu
Srinidhi Varadharajan
Avesta Rastan
Olga Sirbu
Alberto Delaidelli
Randy Van Ommeren
Claudia M Kuzan-Fischer
Laura K Donovan
Florence M G Cavalli
Liam Hendrikse
Cynthia Hawkins
Ana Guerreiro Stucklin
Uri Tabori
Zied Abdullaev
Michelle Ly
Kaitlin Kharas
Matthew L Baker
A Sorana Morrissy
Ning Huang
John M Maris
Juliette Hukin
Kristen Fousek
Tajana Douglas
Alyssa C M Joynt
Polina Balin
Pasqualino De Antonellis
Ahmed Z Gad
Vijay Ramaswamy
Cory Richman
Craig Daniels
Poul H Sorensen
Alex Manno
Borja L Holgado
Livia Garzia
Kevin Bielamowicz
Nabil Ahmed
Stephen C Mack
Antony Michealraj
Mads Daugaard
Dilakshan Srikanthan
Meenakshi Hegde
Sachin A Kumar
Claudia C Faria
Michael D Taylor
Journal: Nature Medicine (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Recurrent medulloblastoma; ependymoma; targeted therapies; cerebrospinal fluid; locoregional therapy
Affiliations: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada., Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada., Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada., Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA., Centre for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA., Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada., Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada., Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada., Cancer Research Program, McGill University Health Centre Research Institute, Montreal, Quebec, Canada., Brain Tumour Program, Children's Cancer Centre and Department of Paediatrics, Baylor College of Medicine, Houston, TX, USA., Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada., Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada., Laboratory of Pathology, National Cancer Institute Centre for Cancer Research, Bethesda, MD, USA., Division of Neurosurgery, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon, Portugal., Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada., Division of Neurology, British Columbia Children's Hospital, Vancouver, British Columbia, Canada., Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada., Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada., Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Centre for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA. ., Centre for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA. ., The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. ., Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada. ., Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada. ., Department of Surgery, Department of Laboratory Medicine and Pathobiology, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. .

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. 

Retracted: No

PubPeer comments:
 There are instances of image duplication in this manuscript. Mice are identical but have varying degrees of luminescence shown. Mice are spread across groups and treatments. These duplications were only analyzed within each figure and not between figures. Affected figures are shown below. ![file] ![file] ![file] ![file] ![file] ![file] ![file] ![file] ![file] , 
 There is the seeming reuse of TRI-CARs(5) data for TRI-CARs + Azacytidine(6) shown below. Potentially, EPHA2 CARs was reused as well. ![file] , 
 #2 It appears that the NT and T cells also overlap. , 
 Here are the top panel figures (MED114FH) which show  re-use of the original (control) figure as control conditions in subsequent experiments - you can see from the shape of the Kaplan Meier curves. They are not re-used in the sense they are re-assigned to a different condition but are re-used as controls. The problem with this is that the later experiments are presented as being independent experiments while clearly they are not: ![file] , 
 #4 The real issue is the renaming of of TRI-CARs to TRI-CARs +Azacytidine. There is no way for the graphs to be accurate since one group has 5 mice and the other says 6. , 
 https: www.nature.com articles s41591-021-01362-1 Author correction citing 49 image duplications. , 
 In several of these instances of  duplication , the same mouse image appears to have a different overlay. Can the authors explain how this happened, since this information does not seem to be in the author correction? That might help some to swallow what essentially amounts to a bulk data replacement. ,