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MICRO 3001 – Infection And Immunity
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MICRO 3001 – Infection And Immunity
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Course Code: MICRO 3001
University: The University Of Adelaide
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Country: Australia
Question:
What is the different criteria used to create chimeric receptors? What are the benefits and disadvantages of using each one. Explain and give examples.What is the clinical importance of chimeric receptors? Explain and document your answer.What are the difficulties molecular and cellular biologist face on understanding and progressing the development of chimeric receptors?
Answer:
Chimeric antigen receptor combines the antigen binding property of the monoclonal antibodies with the self renewal of the T cells. The CARs contains an ecto domain that is been derived from the single chain variable fragment (scFv), an endo-domain and a transmembrane domain. The number of signaling domains determines the classification of the CARs.
Criteria
The two criteria for the development of the CARs are the extracellular domains associated with the intracellular CD3ζ chain and the co-stimulatory domain obtained from the CD28.
Fc gamma chimeric receptors (Fcγ-CRs)-based strategy
1). The Fcγ-CRs consisted of an intracellular tail resulting due to the fusion of the T cell receptor chain with a co- stimulatory molecule. The CAR single chain variable fragments have been replaced with the extracellular portion of the FcγRIIIA (CD16).
Advantages- T- First generation- cells with chimeric receptors are able to overcome the restriction of the major histocompatlibility complex. One advantage is that these CARs can redirect the cytotoxic T- cells against the tumor associated antigen.
Limitations- A single activating signal that is being mediated by the TCRζ chain is not sufficient for the full activation of the T cell and cytokine release.
2). In order to overcome the limitations of the CAR- T cells the co- stimulatory endodomain of the CD28 molecule was linked to the intracellular tail of the CD3ζ-CARs, which are known as the second generation CAR (Caratelli et al., 2017).
Advantages – The second generation T cell improved the functions of the T- cells by providing them with a stronger signal for avoidance of the apoptosis and the T- cell anergy after the binding of the antigen. In comparison to the first generation, the incorporation of the CD28 co-stimulatory domains in to CAR- T cells can lead to the higher secretion of the gamma interferon (CaratellI et al., 2017).
Limitations – The combination of a 4-1BB signaling domain could have further improved the signaling of the CAR cells. The favorable therapeutic results obtained by the dual signaling CAR- T cells helped in the generation of a third generation CAR molecule (Caratelli et al., 2017).
Clinical importance
CAR T- cells are used in cancer treatment. The adoptive transfer of the T-cells expressing the chimeric antigen receptors can be promising because the modified CAR of the T cells can be used to target a tumor associated antigen. The T- cells in this case are collected from the patient and are engineered genetically for expressing the CAR that can be directed towards the antigen on the tumor cells of the patient. The genetically modified T- cells are then infused back.
Challenges faced by the biologists to understand and develop chimeric receptors
One of the primary challenges for developing CAR-T cell therapy is identifying the tumor antigen that has to be targeted safely and effectively (Sadelain et al., 2013). Other challenges for an effective development of the CAR T cell therapy is the lack of the survival and the growth factors (IL2), the presence of the immune-suppressive molecules and the cells.
References:
Caratelli, S., Sconocchia, T., Arriga, R., Coppola, A., Lanzilli, G., Lauro, D., … & Ferrone, S. (2017). FCγ Chimeric Receptor-Engineered T Cells: Methodology, Advantages, Limitations, and Clinical Relevance. Frontiers in immunology, 8, 457.
Sadelain, M., Brentjens, R., & Rivière, I. (2013). The basic principles of chimeric antigen receptor design. Cancer discovery, 3(4), 388-398.
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