Genetically Engineered T-Cells for Malignant Glioma: Overcoming the Barriers to Effective Immunotherapy
Malignant gliomas carry a dismal prognosis. Conventional treatment using chemo- and radiotherapy has limited efficacy with adverse events. Therapy with genetically engineered T-cells, such as chimeric antigen receptor (CAR) T-cells, may represent a promising approach to improve patient outcomes owin...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2019-01-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.03062/full |
| _version_ | 1818859807744983040 |
|---|---|
| author | Pavlina Chuntova Kira M. Downey Bindu Hegde Neil D. Almeida Neil D. Almeida Hideho Okada Hideho Okada Hideho Okada |
| author_facet | Pavlina Chuntova Kira M. Downey Bindu Hegde Neil D. Almeida Neil D. Almeida Hideho Okada Hideho Okada Hideho Okada |
| author_sort | Pavlina Chuntova |
| collection | DOAJ |
| description | Malignant gliomas carry a dismal prognosis. Conventional treatment using chemo- and radiotherapy has limited efficacy with adverse events. Therapy with genetically engineered T-cells, such as chimeric antigen receptor (CAR) T-cells, may represent a promising approach to improve patient outcomes owing to their potential ability to attack highly infiltrative tumors in a tumor-specific manner and possible persistence of the adaptive immune response. However, the unique anatomical features of the brain and susceptibility of this organ to irreversible tissue damage have made immunotherapy especially challenging in the setting of glioma. With safety concerns in mind, multiple teams have initiated clinical trials using CAR T-cells in glioma patients. The valuable lessons learnt from those trials highlight critical areas for further improvement: tackling the issues of the antigen presentation and T-cell homing in the brain, immunosuppression in the glioma microenvironment, antigen heterogeneity and off-tumor toxicity, and the adaptation of existing clinical therapies to reflect the intricacies of immune response in the brain. This review summarizes the up-to-date clinical outcomes of CAR T-cell clinical trials in glioma patients and examines the most pressing hurdles limiting the efficacy of these therapies. Furthermore, this review uses these hurdles as a framework upon which to evaluate cutting-edge pre-clinical strategies aiming to overcome those barriers. |
| first_indexed | 2024-12-19T09:18:03Z |
| format | Article |
| id | doaj.art-b48ab0099be343549d9ff375a177666a |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-19T09:18:03Z |
| publishDate | 2019-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-b48ab0099be343549d9ff375a177666a2022-12-21T20:28:04ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-01-01910.3389/fimmu.2018.03062423816Genetically Engineered T-Cells for Malignant Glioma: Overcoming the Barriers to Effective ImmunotherapyPavlina Chuntova0Kira M. Downey1Bindu Hegde2Neil D. Almeida3Neil D. Almeida4Hideho Okada5Hideho Okada6Hideho Okada7Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United StatesDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United StatesDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United StatesDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United StatesGeorge Washington University School of Medicine and Health Sciences, Washington, DC, United StatesDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United StatesThe Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA, United StatesCancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, United StatesMalignant gliomas carry a dismal prognosis. Conventional treatment using chemo- and radiotherapy has limited efficacy with adverse events. Therapy with genetically engineered T-cells, such as chimeric antigen receptor (CAR) T-cells, may represent a promising approach to improve patient outcomes owing to their potential ability to attack highly infiltrative tumors in a tumor-specific manner and possible persistence of the adaptive immune response. However, the unique anatomical features of the brain and susceptibility of this organ to irreversible tissue damage have made immunotherapy especially challenging in the setting of glioma. With safety concerns in mind, multiple teams have initiated clinical trials using CAR T-cells in glioma patients. The valuable lessons learnt from those trials highlight critical areas for further improvement: tackling the issues of the antigen presentation and T-cell homing in the brain, immunosuppression in the glioma microenvironment, antigen heterogeneity and off-tumor toxicity, and the adaptation of existing clinical therapies to reflect the intricacies of immune response in the brain. This review summarizes the up-to-date clinical outcomes of CAR T-cell clinical trials in glioma patients and examines the most pressing hurdles limiting the efficacy of these therapies. Furthermore, this review uses these hurdles as a framework upon which to evaluate cutting-edge pre-clinical strategies aiming to overcome those barriers.https://www.frontiersin.org/article/10.3389/fimmu.2018.03062/fullT lymphocytebrain cancerGlioblastomaTCR - T cell receptorCAR (chimeric antigen receptor) T cellsGlioma |
| spellingShingle | Pavlina Chuntova Kira M. Downey Bindu Hegde Neil D. Almeida Neil D. Almeida Hideho Okada Hideho Okada Hideho Okada Genetically Engineered T-Cells for Malignant Glioma: Overcoming the Barriers to Effective Immunotherapy Frontiers in Immunology T lymphocyte brain cancer Glioblastoma TCR - T cell receptor CAR (chimeric antigen receptor) T cells Glioma |
| title | Genetically Engineered T-Cells for Malignant Glioma: Overcoming the Barriers to Effective Immunotherapy |
| title_full | Genetically Engineered T-Cells for Malignant Glioma: Overcoming the Barriers to Effective Immunotherapy |
| title_fullStr | Genetically Engineered T-Cells for Malignant Glioma: Overcoming the Barriers to Effective Immunotherapy |
| title_full_unstemmed | Genetically Engineered T-Cells for Malignant Glioma: Overcoming the Barriers to Effective Immunotherapy |
| title_short | Genetically Engineered T-Cells for Malignant Glioma: Overcoming the Barriers to Effective Immunotherapy |
| title_sort | genetically engineered t cells for malignant glioma overcoming the barriers to effective immunotherapy |
| topic | T lymphocyte brain cancer Glioblastoma TCR - T cell receptor CAR (chimeric antigen receptor) T cells Glioma |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.03062/full |
| work_keys_str_mv | AT pavlinachuntova geneticallyengineeredtcellsformalignantgliomaovercomingthebarrierstoeffectiveimmunotherapy AT kiramdowney geneticallyengineeredtcellsformalignantgliomaovercomingthebarrierstoeffectiveimmunotherapy AT binduhegde geneticallyengineeredtcellsformalignantgliomaovercomingthebarrierstoeffectiveimmunotherapy AT neildalmeida geneticallyengineeredtcellsformalignantgliomaovercomingthebarrierstoeffectiveimmunotherapy AT neildalmeida geneticallyengineeredtcellsformalignantgliomaovercomingthebarrierstoeffectiveimmunotherapy AT hidehookada geneticallyengineeredtcellsformalignantgliomaovercomingthebarrierstoeffectiveimmunotherapy AT hidehookada geneticallyengineeredtcellsformalignantgliomaovercomingthebarrierstoeffectiveimmunotherapy AT hidehookada geneticallyengineeredtcellsformalignantgliomaovercomingthebarrierstoeffectiveimmunotherapy |