Emerging Approaches for Solid Tumor Treatment Using CAR-T Cell Therapy
Abstract
:1. Introduction
2. Tumor-Specific CAR-T Cell Immunotherapy
2.1. Hematologic Malignancies
2.2. Solid Tumors
2.2.1. Lung Cancer
2.2.2. Brain Tumor
3. Challenges of CAR-T Cell Therapy for Solid Tumors
3.1. T Cell Intrinsic Factors
3.1.1. T Cell Exhaustion
3.1.2. Toxicity of CAR-T Cells
3.2. T Cell Extrinsic Factors
3.2.1. Immunosuppressive Tumor Microenvironments (TMEs)
3.2.2. Tumor-Associated Antigens
4. Emerging Approaches for the Improvement of CAR-T Cell Therapy
4.1. Redesigning CAR Structure
4.1.1. Multiple CARs with “OR” Strategy
4.1.2. Multiple CARs with “AND” or “NOT” Strategy
4.1.3. Multiple CARs with “IF/THEN” Strategy
4.2. Genome Editing of CAR-T Cell
4.2.1. Knockout of Inhibitory Molecules
4.2.2. Overexpression of T Cell Stimulus Genes
4.2.3. Promoting Inflammatory and Proliferative Activities of CAR-T Cells
4.3. Combination Therapy
4.3.1. Chemotherapy or Other Strategies
4.3.2. Immune Checkpoint Blockade
4.4. Development of CAR-NK Cell Therapy
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Target | CAR-T Cell Mode † | Combination (Strategy) | Malignancy | Preclinical Study | Clinical Trial | Clinical Trial Register | Ref |
---|---|---|---|---|---|---|---|
CD19/CD22 | 41BB | Bispecific CAR-T cell | Leukemia/Lymphoma | - | - | NCT03233854 | [89] |
CD19/CD20 | 41BB | Bispecific CAR-T cell | Leukemia/Lymphoma | - | - | NCT03019055 | [97] |
HER2/IL3Ra2 | CD28 | Pooled CAR-T cells | Glioblastoma model | - | [92] | ||
CD19/CD123 | 41BB | Pooled CAR-T cell | Leukemia model | - | [93] | ||
PSMA/CD19 | PD1/CD28 | Bispecific CAR-T cell | Leukemia model | - | [107] | ||
CD22/CD19 | 41BB | Tandem CAR-T cell | B-ALL | - | - | [94] | |
CD19/MSLN | synNotch/41BB | Bispecific CAR-T cell (synNotch CAR) | Leukemia model | - | [108] | ||
CD19/CD22 | OX40/41BB | Bispecific CAR-T & Pembrolizumab | DLBCL | - | - | NCT03287817 | [95] |
CD20/HER2 | CD28 | Nanobody based tandem CAR-T cell | Leukemia cell | * | [104] | ||
EPHA2 or HER2/GM-CSF | CD28/IL18R | IL18R (MYD88 signaling) | Ewing sarcoma model Osteosarcoma model | - | [137] | ||
GD2 | 41BB/IL7Ra | C7R (STAT5 signaling) | GD2-expressing brain tumors, RR neuroblastoma, other GD2-expressing cancers | - | - | NCT04099797 NCT03635632 | [135] |
PSCA/TGF-β /IL4 | CD28/41BB/IL7Ra | 4/7 ICR | Pancreatic adenocarcinoma model | - | [131] | ||
GPC3/IL4 | CD28/IL21R | 4/21 ICR | IL-4-expressing hepatocarcinoma model | - | [132] | ||
GPC3 | 41BB | IL15, IL21, iCasp9 | Liver cancer Rhabdomyosarcoma | - | - | NCT04715191 | [136] |
N/A | N/A | Knockout of PD1 | Esophageal cancer Renal cell carcinoma Castration resistant prostate cancer Metastatic NSCLC Advanced stage EBV | - - - - - | - - - - - | NCT03081715 NCT02867332 NCT02867345 NCT02793856 NCT03044743 | |
CD19 | CD28 | Knockout of NR4A | Lymphoma model, Melanoma model | - | [120] | ||
CD19 | 41BB | Knockout of TCR/β2 microglobulin/PD1 | ALL model | - | [116] | ||
HER2 | CD28 | Knockout of A2AR | Ovarian carcinoma model | - | [112] | ||
HER2 | CD28 | Knockout of PTPN2 | Breast cancer model | - | [121] | ||
EGFR | 41BB | Knockout of DGK | Glioblastoma model | - | [122] | ||
HER2 | 41BB | Overexpression ofc-Jun | Osteosarcoma model | - | [126] | ||
GPC3 | 41BB | Overexpression ofCXCR2 | Hepatocellular carcinoma model | - | [128] | ||
CD70 | 41BB | Overexpression of CXCR1 or CXCR2 | Glioblastoma model Pancreatic tumor model Ovarian tumor model | - | [129] | ||
PSMA | 41BB | Overexpression of TGF-β DNRII | Prostate cancer | - | - | NCT03089203 | [125] |
CD19 | CD28 (Yescarta®) | Lenzilumab | DLBCL | - | - | ZUMA-19 | [50] |
CD19 | 41BB | Dasatinib | Lymphoma | - | [141] | ||
CD133/HER2 | CD28, 41BB | Galunisertib | Glioblastoma, Breast cancer cell | * | [144] | ||
HER2 | CD28 | Cell-carrier-delivered oncolytic adenovirus | NSCLC | - | - | NCT03740256 | [147] |
EGFR | 41BB | Anti-PD1 scFv secretion | Lung gastric liver cancer | - | - | NCT02862028 | [152,154] |
MSLN | 41BB | Anti-PD1 Ab expression | Refractory prostate cancer | - | - | NCT03030001 | [153] |
MSLN | 41BB | Anti-CTLA4/PD1 Ab expression | Non-hematologic malignancies | - | - | NCT03182803 | [159] |
EGFR | 41BB | Anti-CTLA4/PD1 Ab expression | NSCLC | - | - | NCT03182816 | [160] |
CD19 | 41BB | Pembrolizumab | DLBCL | - | - | NCT02650999 | [161] |
CD19 | 41BB | Pembrolizumab | NHL | - | - | NCT02030834 | [162] |
GD2 | CD28,OX40 | Pembrolizumab | Neuroblastoma | - | - | NCT01822652 | [163] |
CD19 | 41BB | alemtuzumab | B-ALL | - | - | NCT02808442 NCT02746952 | [96] |
N/A | TIL | Ipilimumab | Metastatic melanoma | - | - | NCT02027935 NCT03296137 | [158] |
N/A | TIL | Nivolumab | Metastatic melanoma | - | - | NCT03638375 | |
N/A | TIL | Nivolumab, Pembrolizumab | Metastatic melanoma | - | - | NCT03645928 |
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Chung, H.; Jung, H.; Noh, J.-Y. Emerging Approaches for Solid Tumor Treatment Using CAR-T Cell Therapy. Int. J. Mol. Sci. 2021, 22, 12126. https://doi.org/10.3390/ijms222212126
Chung H, Jung H, Noh J-Y. Emerging Approaches for Solid Tumor Treatment Using CAR-T Cell Therapy. International Journal of Molecular Sciences. 2021; 22(22):12126. https://doi.org/10.3390/ijms222212126
Chicago/Turabian StyleChung, Hyunmin, Haiyoung Jung, and Ji-Yoon Noh. 2021. "Emerging Approaches for Solid Tumor Treatment Using CAR-T Cell Therapy" International Journal of Molecular Sciences 22, no. 22: 12126. https://doi.org/10.3390/ijms222212126