Phase I study of intraventricular infusions of autologous ex vivo expanded NK cells in children with recurrent medulloblastoma and ependymoma.

Gregory K Behbehani, Vidya Gopalakrishnan, Dean A Lee, Wafik Zaky, Rivka Colen, Katy Rezvani, Elizabeth J Shpall, Tagwa Idris, Aikaterini Kotrotsou, Sumit Gupta, Dristhi Ragoonanan, Soumen Khatua, Robin J Nakkula, Prashant Trikha, Heather Meador, Diane D Liu, Michael E Rytting, Jason M Johnson, Leena Ketonen, David I Sandberg, Laurence J N Cooper

Journal: Neuro-oncology 2021;22(8):1214-1225

PMID: 32152626

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Abstract

BACKGROUND

Recurrent pediatric medulloblastoma and ependymoma have a grim prognosis. We report a first-in-human, phase I study of intraventricular infusions of ex vivo expanded autologous natural killer (NK) cells in these tumors, with correlative studies.

METHODS

Twelve patients were enrolled, 9 received protocol therapy up to 3 infusions weekly, in escalating doses from 3 × 106 to 3 × 108 NK cells/m2/infusion, for up to 3 cycles. Cerebrospinal fluid (CSF) was obtained for cellular profile, persistence, and phenotypic analysis of NK cells. Radiomic characterization on pretreatment MRI scans was performed in 7 patients, to develop a non-invasive imaging-based signature.

RESULTS

Primary objectives of NK cell harvest, expansion, release, and safety of 112 intraventricular infusions of NK cells were achieved in all 9 patients. There were no dose-limiting toxicities. All patients showed progressive disease (PD), except 1 patient showed stable disease for one month at end of study follow-up. Another patient had transient radiographic response of the intraventricular tumor after 5 infusions of NK cell before progressing to PD. At higher dose levels, NK cells increased in the CSF during treatment with repetitive infusions (mean 11.6-fold). Frequent infusions of NK cells resulted in CSF pleocytosis. Radiomic signatures were profiled in 7 patients, evaluating ability to predict upfront radiographic changes, although they did not attain statistical significance.

CONCLUSIONS

This study demonstrated feasibility of production and safety of intraventricular infusions of autologous NK cells. These findings support further investigation of locoregional NK cell infusions in children with brain malignancies.

Address: Department of Pediatrics, MD Anderson Cancer Center, Houston.; Ziopharm Oncology and MD Anderson Cancer Center, Houston.; Department of Neurosurgery, MD Anderson Cancer Center, Houston.; Department of Neurosurgery, McGovern Medical School/University of Texas Health Science Center, Houston.; Department of Diagnostic Imaging, MD Anderson Cancer Center, Houston.; Department of Biostatistics, University of Texas MD Anderson Cancer center.; Department of Hematology, Oncology and BMT, Nationwide Children's Hospital, Columbus, Ohio and Department of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.; Department of Cancer Systems Imaging, MD Anderson Cancer Center, Houston.; Department of Radiology, Harvard Medical School.; Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston.; Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.; Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

DOI: 10.1093/neuonc/noaa047

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MeSH Terms: Adolescent, Brain Neoplasms, Cerebellar Neoplasms, Child, Ependymoma, Female, Humans, Infusions, Intraventricular, Killer Cells, Natural, Male, Medulloblastoma, Neoplasm Recurrence, Local