PMID- 28724573 OWN - NLM STAT- MEDLINE DCOM- 20180417 LR - 20220409 IS - 1946-6242 (Electronic) IS - 1946-6234 (Print) IS - 1946-6234 (Linking) VI - 9 IP - 399 DP - 2017 Jul 19 TI - A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. LID - 10.1126/scitranslmed.aaa0984 [doi] LID - eaaa0984 AB - We conducted a first-in-human study of intravenous delivery of a single dose of autologous T cells redirected to the epidermal growth factor receptor variant III (EGFRvIII) mutation by a chimeric antigen receptor (CAR). We report our findings on the first 10 recurrent glioblastoma (GBM) patients treated. We found that manufacturing and infusion of CAR-modified T cell (CART)-EGFRvIII cells are feasible and safe, without evidence of off-tumor toxicity or cytokine release syndrome. One patient has had residual stable disease for over 18 months of follow-up. All patients demonstrated detectable transient expansion of CART-EGFRvIII cells in peripheral blood. Seven patients had post-CART-EGFRvIII surgical intervention, which allowed for tissue-specific analysis of CART-EGFRvIII trafficking to the tumor, phenotyping of tumor-infiltrating T cells and the tumor microenvironment in situ, and analysis of post-therapy EGFRvIII target antigen expression. Imaging findings after CART immunotherapy were complex to interpret, further reinforcing the need for pathologic sampling in infused patients. We found trafficking of CART-EGFRvIII cells to regions of active GBM, with antigen decrease in five of these seven patients. In situ evaluation of the tumor environment demonstrated increased and robust expression of inhibitory molecules and infiltration by regulatory T cells after CART-EGFRvIII infusion, compared to pre-CART-EGFRvIII infusion tumor specimens. Our initial experience with CAR T cells in recurrent GBM suggests that although intravenous infusion results in on-target activity in the brain, overcoming the adaptive changes in the local tumor microenvironment and addressing the antigen heterogeneity may improve the efficacy of EGFRvIII-directed strategies in GBM. CI - Copyright (c) 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. FAU - O'Rourke, Donald M AU - O'Rourke DM AUID- ORCID: 0000-0002-8479-7314 AD - Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Nasrallah, MacLean P AU - Nasrallah MP AUID- ORCID: 0000-0003-4861-0898 AD - Division of Neuropathology, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Desai, Arati AU - Desai A AUID- ORCID: 0000-0002-4849-4703 AD - Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Melenhorst, Jan J AU - Melenhorst JJ AUID- ORCID: 0000-0001-7677-537X AD - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Mansfield, Keith AU - Mansfield K AUID- ORCID: 0000-0002-5191-270X AD - Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA. FAU - Morrissette, Jennifer J D AU - Morrissette JJD AUID- ORCID: 0000-0001-9460-7177 AD - Division of Precision and Computational Diagnostics, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Martinez-Lage, Maria AU - Martinez-Lage M AUID- ORCID: 0000-0002-5859-7562 AD - Division of Neuropathology, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Brem, Steven AU - Brem S AUID- ORCID: 0000-0002-5803-8920 AD - Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Maloney, Eileen AU - Maloney E AD - Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Shen, Angela AU - Shen A AUID- ORCID: 0000-0002-1131-1280 AD - Novartis Oncology, East Hanover, NJ 07936, USA. FAU - Isaacs, Randi AU - Isaacs R AUID- ORCID: 0000-0003-0433-8976 AD - Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA. FAU - Mohan, Suyash AU - Mohan S AD - Division of Neuroradiology, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Plesa, Gabriela AU - Plesa G AUID- ORCID: 0000-0002-4279-5943 AD - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Lacey, Simon F AU - Lacey SF AUID- ORCID: 0000-0003-2882-1962 AD - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Navenot, Jean-Marc AU - Navenot JM AUID- ORCID: 0000-0002-1197-7840 AD - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Zheng, Zhaohui AU - Zheng Z AUID- ORCID: 0000-0002-5253-2477 AD - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Levine, Bruce L AU - Levine BL AUID- ORCID: 0000-0001-6971-8465 AD - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Okada, Hideho AU - Okada H AD - Department of Neurosurgery, University of California, San Francisco, San Francisco, CA 94143, USA. FAU - June, Carl H AU - June CH AUID- ORCID: 0000-0003-0241-3557 AD - Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Brogdon, Jennifer L AU - Brogdon JL AD - Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA. FAU - Maus, Marcela V AU - Maus MV AUID- ORCID: 0000-0002-7578-0393 AD - Cellular Immunotherapy Program, Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, MA 02129, USA. mvmaus@mgh.harvard.edu. LA - eng GR - K08 CA166039/CA/NCI NIH HHS/United States GR - R21 NS083171/NS/NINDS NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PL - United States TA - Sci Transl Med JT - Science translational medicine JID - 101505086 RN - 0 (Receptors, Antigen, T-Cell) RN - 0 (epidermal growth factor receptor VIII) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM CIN - Nat Rev Clin Oncol. 2017 Oct;14(10):586-587. PMID: 28786418 MH - Aged MH - Brain Neoplasms/immunology/metabolism/therapy MH - Cell- and Tissue-Based Therapy/methods MH - ErbB Receptors/immunology/*metabolism MH - Female MH - Glioblastoma/*immunology/metabolism/*therapy MH - Humans MH - Immunohistochemistry MH - Immunotherapy, Adoptive/methods MH - Male MH - Middle Aged MH - Neoplasm Recurrence, Local/*immunology/metabolism/*therapy MH - Receptors, Antigen, T-Cell/immunology/*metabolism PMC - PMC5762203 MID - NIHMS930576 COIS- Competing interests: M.V.M., B.L.L., J.B., J.J.M., C.H.J., and H.O. are inventors on patent application #20170008963 and granted U.S. patent # 9394368 held by the University of Pennsylvania and Novartis that cover the use of CAR T cells targeting EGFRvIII. K.M., R.I., and J.L.B. are employees of Novartis; A.S. is a former employee of Novartis. All other authors declare that they have no competing interests. EDAT- 2017/07/21 06:00 MHDA- 2018/04/18 06:00 PMCR- 2018/01/19 CRDT- 2017/07/21 06:00 PHST- 2016/12/21 00:00 [received] PHST- 2017/05/09 00:00 [accepted] PHST- 2017/07/21 06:00 [entrez] PHST- 2017/07/21 06:00 [pubmed] PHST- 2018/04/18 06:00 [medline] PHST- 2018/01/19 00:00 [pmc-release] AID - 9/399/eaaa0984 [pii] AID - 10.1126/scitranslmed.aaa0984 [doi] PST - ppublish SO - Sci Transl Med. 2017 Jul 19;9(399):eaaa0984. doi: 10.1126/scitranslmed.aaa0984.