Durable regression of Medulloblastoma after regional and intravenous delivery of anti-HER2 chimeric antigen receptor T cells
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Author
Nellan, Anandani
Majzner, Robbie
Lester-McCully, Cynthia M.
Griesinger, Andrea M.
Mulcahy Levy, Jean M.
Foreman, Nicholas K.
Warren, Katherine E.
Lee, Daniel W.
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https://doi.org/10.1186/s40425-018-0340-zMetadata
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Nellan, Anandani, Christopher Rota, Robbie Majzner, Cynthia M. Lester-McCully, Andrea M. Griesinger, Jean M. Mulcahy Levy, Nicholas K. Foreman, Katherine E. Warren, and Daniel W. Lee. 2018. “Durable regression of Medulloblastoma after regional and intravenous delivery of anti-HER2 chimeric antigen receptor T cells.” Journal for Immunotherapy of Cancer 6 (1): 30. doi:10.1186/s40425-018-0340-z. http://dx.doi.org/10.1186/s40425-018-0340-z.Abstract
Background: Standard-of-care therapies for treating pediatric medulloblastoma have long-term side effects, even in children who are cured. One emerging modality of cancer therapy that could be equally effective without such side effects would be chimeric antigen receptor (CAR) T cells. Knowing that human epidermal growth factor receptor 2 (HER2) is overexpressed in many medulloblastomas and has been used as a CAR T target before, we sought to evaluate the efficacy of more sophisticated anti-HER2 CAR T cells, as well as the feasibility and efficacy of different routes of delivering these cells, for the treatment of pediatric medulloblastoma. Methods: Daoy, D283 and D425 medulloblastoma cell lines were characterized by flow cytometry to evaluate HER2 expression. Anti-tumor efficacy of HER2-BBz-CAR T cells in vitro was performed using cytokine release and immune cytotoxicity assays compared to control CD19 CAR T cells. In vivo, Daoy and D283 tumor cells were orthotopically implanted in the posterior fossa of NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice and treated with regional or intravenous HER2-BBz-CAR T cells or control CD19 CAR T cells. Non-human primates (NHPs) bearing ventricular and lumbar reservoirs were treated with target autologous cells bearing extracellular HER2 followed by autologous HER2-CAR T cells intraventricularly. Cerebrospinal fluid and blood were collected serially to measure the persistence of delivered cells and cytokines. Results: HER2-BBz-CAR T cells effectively clear medulloblastoma orthotopically implanted in the posterior fossa of NSG mice via both regional and intravenous delivery in xenograft models. Intravenous delivery requires a log higher dose compared to regional delivery. NHPs tolerated intraventricular delivery of autologous cells bearing extracellular HER2 followed by HER2-BBz-CAR T cells without experiencing any systemic toxicity. Conclusions: HER2-BBz-CAR T cells show excellent pre-clinical efficacy in vitro and in mouse medulloblastoma models, and their intraventricular delivery is feasible and safe in NHPs. A clinical trial of HER2-BBz-CAR T cells directly delivered into cerebrospinal fluid should be designed for patients with relapsed medulloblastoma. Electronic supplementary material The online version of this article (10.1186/s40425-018-0340-z) contains supplementary material, which is available to authorized users.Other Sources
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