Improving CAR T-Cell Persistence
Over the last decade remarkable progress has been made in enhancing the efficacy of CAR T therapies. However, the clinical benefits are still limited, especially in solid tumors. Even in hematological settings, patients that respond to CAR T therapies remain at risk of relapsing due to several facto...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/19/10828 |
| _version_ | 1797516192389267456 |
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| author | Violena Pietrobon Lauren Anne Todd Anghsumala Goswami Ofir Stefanson Zhifen Yang Francesco Marincola |
| author_facet | Violena Pietrobon Lauren Anne Todd Anghsumala Goswami Ofir Stefanson Zhifen Yang Francesco Marincola |
| author_sort | Violena Pietrobon |
| collection | DOAJ |
| description | Over the last decade remarkable progress has been made in enhancing the efficacy of CAR T therapies. However, the clinical benefits are still limited, especially in solid tumors. Even in hematological settings, patients that respond to CAR T therapies remain at risk of relapsing due to several factors including poor T-cell expansion and lack of long-term persistence after adoptive transfer. This issue is even more evident in solid tumors, as the tumor microenvironment negatively influences the survival, infiltration, and activity of T-cells. Limited persistence remains a significant hindrance to the development of effective CAR T therapies due to several determinants, which are encountered from the cell manufacturing step and onwards. CAR design and ex vivo manipulation, including culture conditions, may play a pivotal role. Moreover, previous chemotherapy and lymphodepleting treatments may play a relevant role. In this review, the main causes for decreased persistence of CAR T-cells in patients will be discussed, focusing on the molecular mechanisms underlying T-cell exhaustion. The approaches taken so far to overcome these limitations and to create exhaustion-resistant T-cells will be described. We will also examine the knowledge gained from several key clinical trials and highlight the molecular mechanisms determining T-cell stemness, as promoting stemness may represent an attractive approach to improve T-cell therapies. |
| first_indexed | 2024-03-10T06:58:43Z |
| format | Article |
| id | doaj.art-40559d071a294bc4b3b824749bdb2c17 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T06:58:43Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-40559d071a294bc4b3b824749bdb2c172023-11-22T16:16:02ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-10-0122191082810.3390/ijms221910828Improving CAR T-Cell PersistenceViolena Pietrobon0Lauren Anne Todd1Anghsumala Goswami2Ofir Stefanson3Zhifen Yang4Francesco Marincola5Refuge Biotechnologies, Inc., Menlo Park, CA 94025, USADepartment of Biology, Faculty of Science, University of Waterloo, Waterloo, ON N2L 3G1, CanadaRefuge Biotechnologies, Inc., Menlo Park, CA 94025, USARefuge Biotechnologies, Inc., Menlo Park, CA 94025, USARefuge Biotechnologies, Inc., Menlo Park, CA 94025, USAKite Pharma, Inc., Santa Monica, CA 90404, USAOver the last decade remarkable progress has been made in enhancing the efficacy of CAR T therapies. However, the clinical benefits are still limited, especially in solid tumors. Even in hematological settings, patients that respond to CAR T therapies remain at risk of relapsing due to several factors including poor T-cell expansion and lack of long-term persistence after adoptive transfer. This issue is even more evident in solid tumors, as the tumor microenvironment negatively influences the survival, infiltration, and activity of T-cells. Limited persistence remains a significant hindrance to the development of effective CAR T therapies due to several determinants, which are encountered from the cell manufacturing step and onwards. CAR design and ex vivo manipulation, including culture conditions, may play a pivotal role. Moreover, previous chemotherapy and lymphodepleting treatments may play a relevant role. In this review, the main causes for decreased persistence of CAR T-cells in patients will be discussed, focusing on the molecular mechanisms underlying T-cell exhaustion. The approaches taken so far to overcome these limitations and to create exhaustion-resistant T-cells will be described. We will also examine the knowledge gained from several key clinical trials and highlight the molecular mechanisms determining T-cell stemness, as promoting stemness may represent an attractive approach to improve T-cell therapies.https://www.mdpi.com/1422-0067/22/19/10828persistenceexhaustionCARlymphodepletionculturing conditionsstemness |
| spellingShingle | Violena Pietrobon Lauren Anne Todd Anghsumala Goswami Ofir Stefanson Zhifen Yang Francesco Marincola Improving CAR T-Cell Persistence International Journal of Molecular Sciences persistence exhaustion CAR lymphodepletion culturing conditions stemness |
| title | Improving CAR T-Cell Persistence |
| title_full | Improving CAR T-Cell Persistence |
| title_fullStr | Improving CAR T-Cell Persistence |
| title_full_unstemmed | Improving CAR T-Cell Persistence |
| title_short | Improving CAR T-Cell Persistence |
| title_sort | improving car t cell persistence |
| topic | persistence exhaustion CAR lymphodepletion culturing conditions stemness |
| url | https://www.mdpi.com/1422-0067/22/19/10828 |
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