Modern Advances in CARs Therapy and Creating a New Approach to Future Treatment
Abstract
:1. Introduction
2. CARs
3. CAR-T Cytotoxic Mechanism
4. CAR-T Therapy
5. Limitations of CAR-T Cells Therapy
6. CAR-NK Cytotoxic Mechanism
7. CAR-NK Therapy
8. Sources of NK Cells
9. Limitations CAR-NK Cells Therapy
10. Nanobodies Based CARs
11. CAR Exosomes in Cancer Therapy as a Novel Anti-Cancer Strategy
12. Comparison to Other Immunotherapies
13. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Generic Name | Brand Name | Target Antigen | Targeted Disease | Patient Population |
---|---|---|---|---|
Tisagenlecleucel | Kymriah | CD19 | B-cell acute lymphoblastic leukemia (ALL) | Children and young adults with refractory or relapsed B-cell ALL |
B-cell non-Hodgkin lymphoma (NHL) | Adults with relapsed or refractory B-cell NHL | |||
Axicabtagene ciloleucel | Yescarta | CD19 | B-cell non-Hodgkin lymphoma (NHL) | Adults with relapsed or refractory B-cell NHL |
Follicular lymphoma | Adults with relapsed or refractory follicular lymphoma | |||
Brexucabtagene autoleucel | Tecartus | CD19 | B-cell acute lymphoblastic leukemia (ALL) | Adults with refractory or relapsed B-cell ALL |
Mantle cell lymphoma (MCL) | Adults with refractory or relapsed MCL | |||
Lisocabtagene maraleucel | Breyanzi | CD19 | B-cell non-Hodgkin lymphoma (NHL) | Adults with relapsed or refractory B-cell NHL |
Ciltabtagene autoleucel | Carvykti | BCMA | Multiple myeloma | Adults with relapsed or refractory multiple myeloma |
Idecabtagene vicleucel | Abecma | BCMA | Multiple myeloma | Adults with relapsed or refractory multiple myeloma |
CAR-T Cells | ||
---|---|---|
Sources | Different mixes of helper CD4+ and cytotoxic CD8+ cells T cells. | |
Autologous T cells | Allogeneic T cells | |
Quality of source | Limitations of quality and quantity T cell number. Various donors of T cells. | Multiple T cell sources from many healthy donors (PB or UCB). Standardized source of cell. |
Manufacture | Risk of manufacture in a group for heavily pretreated patients. The limited potency of the CAR-T cellular product is because the patient’s T lymphocytes treated with chemotherapy are more differentiated with lower proliferation capacity and rapid exhaustion. | The starting material is high quality from a healthy donor. |
Risk of contamination | Risk of contamination with cancer cells in patient blood. | Minimal risks of cancer cell contamination, source form healthy donor blood. |
Persistence | Increased in vivo persistence compared with allogeneic CAR-T cells due to lack of immune rejection from the host. | Decreased in vivo persistence due to higher immunogenicity. |
Risk of GVHD | Low | High |
Scalability | Low-personalized product for one patient | High—one product for many patients |
Acute side effects | It may cause GVHD, CRS and neurotoxicity. | Barely cause GVHD, may even protect against GVHD. Lack of CRS and neurotoxicity. |
Mechanism | CAR-NK Cells | CAR-T Cells |
---|---|---|
Chimeric antigen receptor | CARs cells can aim for specific tumor antigen | |
Antigen presentation | NK cells can specifically recognize the cells that lack the expression of self-MHC class I molecules [65]. Enhancing the antigen presentation to T cells by killing the immature DC while promoting the IFN g and TNF-a mediated maturation of DC [66]. | They can recognize antigens regardless of MHC presentation. However, they are limited to the recognition of structures expressed at the surface [28,29]. |
Transduction efficiency | lower | higher |
In vivo persistence | worse | better |
Fas/FasL | The Fas-FasL is a major apoptosis pathway via caspase-dependent activation. The antigen-negative cancer cells can be targeted via FAS and Fas L axis, independent of presenting death receptors by the cancer cell. It is estimated that the functions of this pathway may be pivotal in the heterogeneous environment of the tumor [38,39]. | |
Cytolytic granules | CARs cells lyse the antigen-positive cancer cells mainly by the cytolytic granules. The perforins are inducing pore formation in the cancer membrane, forming the access for granzymes. In the cytoplasm, they could induce apoptotic cell death in a caspase-dependent or independent way. Therefore, cytolytic degranulation is assumed to be the most important mechanism of cell killing by CAR-T cells [6]. Cytokine production induces cell death via secondary mechanisms, such as enhancing CARs, Fas, or TRAIL pathways. They trigger several anti-tumor immune responses, including the enhancement of the cytotoxic response, recruitment, and activation of innate immune cells [67]. | |
There were attempts to use ectopically expressed chimeric granzyme B. This approach could enhance NK-cell degranulation and efficient producing cytolytic granules [68,69]. | Cytolytic granules secretion by CAR-T cells mediates tumor lysis via upregulating IFN-gamma on stromal cells [41]. That leads to immune cell modulations, such as the polarization of macrophages to the antitumoral M1 phenotype [42]. | |
Checkpoint inhibitors | Prevention of the interaction of inhibitory receptors with their respective ligands leads to inhibition of NK cell suppression [70]. Additionally, checkpoint molecules can enable tumor escape from NK cell vigilance [71]. | CAR-T cells can secrete immune checkpoint inhibitors to overcome immunosuppression of tumors (e.g., anti-PD-1/PD-L1/CTLA-4) for enhanced strength, effectiveness, and persistence of CAR-T therapy [72,73,74,75,76]. |
CAR-T Cells | CAR-NK Cells | ||
---|---|---|---|
Advantages | Disadvantages | Advantages | Disadvantages |
|
|
|
|
Event | CAR-T Cells | CAR-T Cell-Derived Exosomes |
---|---|---|
Cross the blood barrier | − | ++ |
Cytokine releasing syndrome | ++ | − |
Neurotoxicity and GvHD | ++ | − |
Reprograming and act against suppressive cells | − | ++ |
Efficiency against solid tumors | + | ++ |
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Sadowski, K.; Olejarz, W.; Basak, G. Modern Advances in CARs Therapy and Creating a New Approach to Future Treatment. Int. J. Mol. Sci. 2022, 23, 15006. https://doi.org/10.3390/ijms232315006
Sadowski K, Olejarz W, Basak G. Modern Advances in CARs Therapy and Creating a New Approach to Future Treatment. International Journal of Molecular Sciences. 2022; 23(23):15006. https://doi.org/10.3390/ijms232315006
Chicago/Turabian StyleSadowski, Karol, Wioletta Olejarz, and Grzegorz Basak. 2022. "Modern Advances in CARs Therapy and Creating a New Approach to Future Treatment" International Journal of Molecular Sciences 23, no. 23: 15006. https://doi.org/10.3390/ijms232315006