Revolutionizing Cancer Treatments through Stem Cell-Derived CAR T Cells for Immunotherapy: Opening New Horizons for the Future of Oncology
Abstract
:1. Introduction
2. Generation of Allogeneic CAR T Cells
3. Cord Blood-Derived CAR T Cells
4. iPSC-Derived CAR T Cells
5. CAR T-Cell Structure and Design
6. Selection of Optimized scFv
7. Enhancing the Allogenicity and Efficacy of CAR T Cells
8. Future Direction and Scope
9. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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CAR T-Cell Therapy Name | Target Antigen | Indication | Manufacturer | Reference |
---|---|---|---|---|
Kymriah (tisagenlecleucel) | CD19 | B-cell acute lymphoblastic leukemia (ALL) | Novartis | FDA approval (2017) [33,34] |
Yescarta (axicabtagene ciloleucel) | CD19 | Large B-cell lymphoma | Kite Pharma/Gilead | FDA approval (2017) [35] |
Kymriah (tisagenlecleucel) | CD19 | Large B-cell lymphoma | Novartis | FDA approval (2018) [34] |
Yescarta (axicabtagene ciloleucel) | CD19 | Follicular lymphoma | Kite Pharma/Gilead | FDA approval (2021) [36] |
Tecartus (brexucabtagene autoleucel) | CD19 | Mantle cell lymphoma | Kite Pharma/Gilead | FDA approval (2020) [37] |
Breyanzi (lisocabtagene maraleucel) | CD19 | Large B-cell lymphoma | Bristol-Myers Squibb | FDA approval (2021) [38] |
Abecma (idecabtagene vicleucel) | BCMA | Multiple myeloma | Bristol-Myers Squibb | FDA approval (2021) [39] |
Carvykti (ciltacabtagene autoleucel) | BCMA | Relapsed or refractory multiple myeloma | Johnson & Johnson/Legend Biotech | FDA approval (2022) [40] |
Domains | Protein Region |
---|---|
Intracellular | CD3ζ, CD28, and 41BB |
Transmembrane | CD3ζ, CD28, 41BB, CD8α, FcγRIIIA, TCRαβ, and DAP12 |
Hinge domain | CD8α, CD28, IgG4, IgG2, IgG1, and DAP12 |
Extracellular | VH-VL, VL-VH, and VH |
Criteria | Description |
---|---|
Eligibility of donor | Donors must be screened for transmissible diseases as per FDA regulations (21 CFR 1271). |
Transduction efficiency | Efficiency of gene transduction should be monitored to ensure correct expression of the CAR construct in T cells. |
Vector copy number (VCN) | VCN per cell must be monitored and controlled, generally targeting 1–5 copies per cell to avoid toxicity and insertional mutagenesis. |
T-cell expansion | Post-transduction, T cells are expanded in a controlled environment, ensuring high viability and potency. |
Purity check | The final product must meet specific purity (e.g., CD3+ cells) and identity (e.g., CAR expression) standards. |
Potency assays | Potency assays must be performed to ensure CAR T cells are capable of recognizing and killing target cancer cells. |
Safety check | Sterility, endotoxin levels, and mycoplasma testing must be performed to ensure no contamination during production. |
Viability of CAR T cells | The FDA mandates the minimum viability (usually > 70%) of CAR T cells at the time of infusion. |
Cryopreservation | Cells are typically cryopreserved for shipment and storage; freezing methods must ensure cell stability post-thaw. The concentration of DMSO must be ≤10% v/v; however, ≤5% v/v is often preferred to further reduce DMSO-related cytotoxicity. |
Release criteria | The final product must meet pre-defined release criteria, including CAR expression, viability, identity, purity, and vector copy number (VCN). |
Adventitious agent or other contaminants | Testing is required to confirm that the product is free from unintended viruses or contaminants. |
Preclinical studies | Preclinical models must demonstrate safety and efficacy before clinical trials can commence. |
Clinical manufacturing | Must adhere to Good Manufacturing Practice (GMP) guidelines (21 CFR Parts 210 and 211), including controlled and reproducible processes. |
Labeling | CAR T-cell products must have clear labeling for identity, dose, and instructions as per FDA labeling regulations (21 CFR Part 610). |
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Mishra, H.K.; Kalyuzhny, A. Revolutionizing Cancer Treatments through Stem Cell-Derived CAR T Cells for Immunotherapy: Opening New Horizons for the Future of Oncology. Cells 2024, 13, 1516. https://doi.org/10.3390/cells13181516
Mishra HK, Kalyuzhny A. Revolutionizing Cancer Treatments through Stem Cell-Derived CAR T Cells for Immunotherapy: Opening New Horizons for the Future of Oncology. Cells. 2024; 13(18):1516. https://doi.org/10.3390/cells13181516
Chicago/Turabian StyleMishra, Hemant K., and Alex Kalyuzhny. 2024. "Revolutionizing Cancer Treatments through Stem Cell-Derived CAR T Cells for Immunotherapy: Opening New Horizons for the Future of Oncology" Cells 13, no. 18: 1516. https://doi.org/10.3390/cells13181516