Cutting-Edge CAR Engineering: Beyond T Cells
Abstract
:1. Introduction: Adoptive T Cell Therapy (ACT)
2. Myeloid Cells Sustaining the Tumour Microenvironment
3. Modulation of Myeloid Cells as a Therapeutic Strategy
3.1. Reprogramming of Myeloid Cells to Acquire Proinflammatory Properties
3.2. Targeting the Myeloid Cell Composition within the TME through Enhanced Differentiation, Proliferation and Recruitment
3.3. Functional Blockade of Immune-Suppressive Myeloid Cells
3.4. Myeloid Cells Vaccines
3.5. Immunometabolic Strategies
4. New Era of CAR-Engineered Cell Therapies for Innate Immune Cells
New Era of CAR-Engineered Cell Therapies for Innate Immune Cells
5. Preclinical and Clinical Development of CAR-Innate Immune Cell Strategies
5.1. Preclinical Development of CAR-Innate Immune Cell Strategies
5.2. Clinical Development of CAR-Myeloid Strategies
5.2.1. NCT04660929
5.2.2. NCT05007379, the CARMA-2101 Study
5.2.3. NCT05138458, the IMAGINE Study
6. Conclusions and Key Ideas
- Adoptive T cell therapy (APC) has emerged as a promising therapeutic strategy to treat cancer that might overcome the clinical limitations of immune checkpoint blockade immunotherapies.
- CAR-T cell therapies are demonstrating success for the treatment of haematological malignancies, but these therapies fail for the treatment of solid tumours. In order to overcome these critical barriers, novel cutting-edge CAR strategies are being developed, such as the genetic engineering of other key innate immune cell types such as NK cells, macrophages, monocytes and other myeloid populations.
- CD3ζ, CD28, 4-1BB, Megf10, MerTK, PI3K, CD86, CD147, TLR2, TLR4 and TLR6 are being used as intracellular signalling domains for CAR-M generation, to enhance its phagocytic capacities.
- Advanced strategies need to be developed by understanding the properties of myeloid cells in the tumour. A clear example is multi-omics data analysis that provides insights into myeloid cell phenotypes.
- CAR-M has been demonstrated in vitro and in vivo to suppress tumour growth in vivo with low toxicity, prolong survival, prevent metastasis, induce T cell infiltration, and induce systemic anti-tumour immunity.
- In the new CAR-M generation, the adaptation of cytokine receptor domains is required to further improve the immune modulation and tumour killing capabilities of CAR-M products.
- CAR-M therapies are being developed in three clinical trials.
- CAR-NK therapies are being developed in 41 clinical trials.
- While recent works have demonstrated the feasibility of using CAR-immune innate cells as a therapeutic product, the mechanisms by which they function in the TME and how this may lead to tumour rejection remain unclear. To utilise this approach, we need to understand more about how CAR-immune innate cells function within tumours and can be manipulated to generate.
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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CAR-T | CAR-NK | CAR-M |
---|---|---|
CD3ζ | CD3ζ | CD3ζ |
CD3γ | CD28 | CD28 |
CD28 | 4−1ΒΒ | 4−1ΒΒ |
4−1ΒΒ | CD137 | Megf10 |
OX40 | 2B4 | MerTK |
CD20 | DAP10 | PI3K |
CD137 | DAP12 | CD86 |
ICOS | NKG2D | CD147 |
CD40 | CD244 | TLR2 |
CD27 | Etc. | TLR4 |
Etc. | TLR6 |
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Chocarro, L.; Blanco, E.; Fernández-Rubio, L.; Arasanz, H.; Bocanegra, A.; Echaide, M.; Garnica, M.; Ramos, P.; Piñeiro-Hermida, S.; Vera, R.; et al. Cutting-Edge CAR Engineering: Beyond T Cells. Biomedicines 2022, 10, 3035. https://doi.org/10.3390/biomedicines10123035
Chocarro L, Blanco E, Fernández-Rubio L, Arasanz H, Bocanegra A, Echaide M, Garnica M, Ramos P, Piñeiro-Hermida S, Vera R, et al. Cutting-Edge CAR Engineering: Beyond T Cells. Biomedicines. 2022; 10(12):3035. https://doi.org/10.3390/biomedicines10123035
Chicago/Turabian StyleChocarro, Luisa, Ester Blanco, Leticia Fernández-Rubio, Hugo Arasanz, Ana Bocanegra, Miriam Echaide, Maider Garnica, Pablo Ramos, Sergio Piñeiro-Hermida, Ruth Vera, and et al. 2022. "Cutting-Edge CAR Engineering: Beyond T Cells" Biomedicines 10, no. 12: 3035. https://doi.org/10.3390/biomedicines10123035