State of the Art in CAR-T Cell Therapy for Solid Tumors: Is There a Sweeter Future?
Abstract
:1. Introduction
2. Approved CAR-T Cell Therapies
3. Challenges and Limitations of CAR-T Cell Therapy in Solid Tumors
3.1. Antigen Loss
3.2. T Cell Exhaustion
3.3. T Cell Trafficking and Tumor Infiltration
3.3.1. Local Administration
3.3.2. Expression of Chemokine Receptors
3.3.3. CAR-T Cells Engineered to Better Penetrate the Tumor Stroma
3.4. Immunosuppressive Tumor Microenvironment (TME)
3.5. Intrinsic Resistance to CAR-T Killing
3.6. Combination Strategies to Improve CAR-T Therapies
3.6.1. Chemotherapy
3.6.2. Radiotherapy
3.6.3. Oncolytic Viruses
3.6.4. Immune Checkpoints Inhibitors
3.7. On-Target Off-Tumor Toxicity
4. CAR-T Cell Targets in Solid Tumors
4.1. Protein Antigens
4.1.1. HER2
4.1.2. EGFR
4.1.3. CEA
4.1.4. ROR1
4.1.5. NKG2D Ligands
4.1.6. B7-H3
4.1.7. CD70
4.1.8. CLDN18.2
4.1.9. Mesothelin
4.2. Carbohydrate Antigens
4.2.1. Heparan Sulfate Proteoglycans (HSPGs)
4.2.2. Mucin Glycans
4.2.3. Gangliosides
4.2.4. Blood-Group Related Lewis Antigens
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Protein Antigens | |||
---|---|---|---|
Antigen | Total | CAR-T Interventions | Phase |
Mesothelin (MSLN) | 20 | Anti-MSLN CAR-T cells, anti-CTLA4/PD-1 expressing MSLN CAR-T cells, CD40L expressing MSLN CAR-T cells, logic-gated MSLN CAR-T cells inhibited by HLA-A*02 | I/II |
HER2 | 6 | Anti-HER2 CAR-T cells, oncolytic viruses + CAR-T cells, memory-enriched anti-HER2 CAR-T cells | I |
CEA | 10 | Anti-CEA CAR-T cells, logic-gated CEA CAR-T cells inhibited by HLA-A*02 | I/II |
ROR1 | 5 | Anti-ROR1 CAR-T cells, anti-ROR1 CAR-T cells expressing mbIL15 and PD-1 downregulation | I/II |
B7-H3 | 7 | Anti-B7H3 CAR-T cells, dual anti-EGFR/B7H3 CAR-T cells, dual anti-CD19/B7H3 CAR-T cells with/without pembrolizumab | I |
BT-001 | 2 | Anti BT-001 CAR-T cells | I |
CD70 | 7 | Anti-CD70 CAR-T cells | I/II |
NKG2DL | 8 | Anti-NKG2DL CAR-T cells, dual anti-NKG2DL/CLDN18.2 CAR-T cells, allogeneic/haploidentical anti-NKG2DL CAR γδ T cells, universal dual anti-NKG2DL-NKp44 CAR-T cells | I |
EGFR | 6 | Dual anti-EGFR/B7H3 CAR-T cells, anti-CTLA-4/PD-1 expressing EGFR CAR-T cells, TGFβR knockout anti-EGFR CAR-T cells, dual anti-EGFR/CD19 CAR-T cells | I/II |
CLDN18.2 | 14 | Anti-CLDN18.2 CAR-T cells, dual anti-CLDN18.2/PD-L1 CAR-T cells, dual anti-NKG2DL/CLDN18.2 CAR-T cells, anti-CLDN18.2 CAR-T cells with co-expression of cytokines, iPD-1-CLDN18.2 CAR-T cells | I/II |
PD-L1 | 2 | dual anti-CLDN18.2/PD-L1 CAR-T cells, dual anti-VEGFR1/PD-L1 CAR-T cells | I |
VEGFR1 | 1 | dual anti-VEGFR1/PD-L1 CAR-T cells | I |
CD22 | 1 | Anti-PD-L1 armored anti-CD22 CAR-T/CAR-TILs | I |
EpCAM | 2 | Anti-EpCAM CAR-T cells | I |
TM4SF1 | 1 | Anti-TM4SF1 CAR-T cells | N/A |
Nectin4 | 1 | Anti-Nectin4/FAP CAR-T cells expressing IL-7 and CCL19 or/and IL-12 | I |
CLDN6 | 1 | Anti-CLDN6 CAR-T cells with or without a liposomal formulation containing CLDN6 RNA | I/II |
PSMA | 1 | Dual anti-GD2/PSMA CAR-T cells | I/II |
ROR2 | 1 | Anti-ROR2 CAR-T cells | I |
EphA-2 | 2 | Anti-EphA-2 CAR-DCs loaded with TP53/KRAS mutant peptide combine with anti-PD-1/CTLA4 antibodies | I |
HLA-G | 2 | Anti-HLA-G CAR-T cells, anti-HLA-G-BiTE γδ CAR-T cells, | I/II |
GCC | 2 | Anti-GCC CAR-T cells | N/A |
Carbohydrate antigens | |||
Antigen | Total | CAR-T interventions | Phase |
MUC1 | 7 | Anti-MUC1 CAR-T cells, anti-CTLA-4/PD-1 expressing MUC1 CAR-T cells, allogeneic anti-MUC1 CAR-T cells, PD-1 knockout anti-MUC1 CAR-T cells | I/II |
GPC3 | 6 | Anti-GPC3 CAR-T cells, IL-15 armored anti-GPC3 CAR-T cells, IL-15 and IL-21 armored anti-GPC3 CAR-T cells, anti-GPC3 CAR-T cells with exogenous GOT2 expression | I/II |
Lewis Y | 1 | Anti-Lewis Y CAR-T cells | I |
GD2 | 6 | Anti-GD2 CAR-T cells, Dual anti-GD2/PSMA CAR-T cells, anti-GD2 CAR-T cells with an inducible apoptotic caspase 9 domain (iC9), OX40/CD28 expressing iC9 anti-GD2 CAR-T cells, C7R expressing anti-GD2 CAR-T Cells | I/II |
Trop-2 | 1 | Anti-Trop-2 CAR-T cells | I/II |
CD138 | 1 | Anti-CD138 CAR-T cells | I |
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Amorós-Pérez, B.; Rivas-Pardo, B.; Gómez del Moral, M.; Subiza, J.L.; Martínez-Naves, E. State of the Art in CAR-T Cell Therapy for Solid Tumors: Is There a Sweeter Future? Cells 2024, 13, 725. https://doi.org/10.3390/cells13090725
Amorós-Pérez B, Rivas-Pardo B, Gómez del Moral M, Subiza JL, Martínez-Naves E. State of the Art in CAR-T Cell Therapy for Solid Tumors: Is There a Sweeter Future? Cells. 2024; 13(9):725. https://doi.org/10.3390/cells13090725
Chicago/Turabian StyleAmorós-Pérez, Beatriz, Benigno Rivas-Pardo, Manuel Gómez del Moral, José Luis Subiza, and Eduardo Martínez-Naves. 2024. "State of the Art in CAR-T Cell Therapy for Solid Tumors: Is There a Sweeter Future?" Cells 13, no. 9: 725. https://doi.org/10.3390/cells13090725