A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma
| العنوان: | A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma |
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| المؤلفون: | Zhaohui Zheng, Carl H. June, Maria Martinez-Lage, Suyash Mohan, Jennifer J.D. Morrissette, Jennifer Brogdon, Randi Isaacs, Keith Mansfield, Simon F. Lacey, Eileen Maloney, J. Joseph Melenhorst, Donald M. O'Rourke, Angela Shen, MacLean Nasrallah, Jean-Marc Navenot, Steven Brem, Marcela V. Maus, Gabriela Plesa, Arati Desai, Hideho Okada, Bruce L. Levine |
| المصدر: | Science translational medicine, vol 9, iss 399 |
| بيانات النشر: | American Association for the Advancement of Science (AAAS), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, medicine.medical_treatment, Adoptive, Cell- and Tissue-Based Therapy, Medical and Health Sciences, Immunotherapy, Adoptive, 0302 clinical medicine, Stem Cell Research - Nonembryonic - Human, Receptors, Medicine, Epidermal growth factor receptor, Cancer, biology, Brain Neoplasms, General Medicine, Biological Sciences, Middle Aged, Immunohistochemistry, ErbB Receptors, Cytokine release syndrome, medicine.anatomical_structure, Local, Antigen, 030220 oncology & carcinogenesis, Toxicity, Female, Immunotherapy, Development of treatments and therapeutic interventions, Biotechnology, T cell, Receptors, Antigen, T-Cell, Vaccine Related, 03 medical and health sciences, Rare Diseases, Clinical Research, Humans, Aged, Tumor microenvironment, 5.2 Cellular and gene therapies, business.industry, Neurosciences, T-Cell, Stem Cell Research, medicine.disease, Chimeric antigen receptor, Brain Disorders, Brain Cancer, Neoplasm Recurrence, 030104 developmental biology, Immunology, biology.protein, Immunization, Neoplasm Recurrence, Local, Glioblastoma, business |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| تدمد: | 1946-6242 1946-6234 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6b6e35a35a57d94f444de06bf9d7b707Test https://doi.org/10.1126/scitranslmed.aaa0984Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....6b6e35a35a57d94f444de06bf9d7b707 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19466242 19466234 |
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