Next generation armored CAR-T cells with a drug inducible cytokine circuit

Research Article
Open access

Next generation armored CAR-T cells with a drug inducible cytokine circuit

David Drew 1 , Xinyan Li 2* , Michael Su 3 , Qingmei Wang 4
  • 1 University of Houston    
  • 2 St. Mildred’s Lightbourn School    
  • 3 McMaster University    
  • 4 Worcester Academy    
  • *corresponding author lisali3297@gmail.com
Published on 20 December 2023 | https://doi.org/10.54254/2753-8818/24/20231150
TNS Vol.24
ISSN (Print): 2753-8826
ISSN (Online): 2753-8818
ISBN (Print): 978-1-83558-221-3
ISBN (Online): 978-1-83558-222-0

Abstract

Immunotherapies which direct the body’s own immune system against tumors are a safer and more efficacious alternative to other types of cancer treatments. Chimeric Antigen Receptor or CAR T cell therapy has emerged at the forefront of contemporary cancer immunotherapy research and is highly specific for a wide range of cancer types, resulting in improved patient outcomes. Early generations of CAR T cells were ineffective and failed to proliferate due to lack of costimulatory signals and immunosuppression within the tumor microenvironment (TME), but later generations of “armored” CAR T cells added costimulatory receptor domains and constitutive expression of stimulatory immunocytokines to ameliorate this. However, increased aggressiveness in T cells comes with issues such as off-site toxicity, fails to address relapse due to immune evasion, and combined with the prohibitive cost of engineering CAR T cells limit the efficacy of the treatment. Next generation CAR T-cells address these problems with the engineering of synthetic biological circuits that provide selective control over immune function in response to inducers. In this research proposal, we design a next generation armored CAR T cell with a small molecule inducible cytokine circuit, combining different synthetic biology approaches from previous research on CAR T cells to enhance the safety of the therapy by providing a reversible, safe, and rapid method of modulating CAR T cell stimulation.

Keywords:

Armored CAR T-Cells, synNotch Receptor, Synthetic Cytokine Circuit, Research Proposal

Drew,D.;Li,X.;Su,M.;Wang,Q. (2023). Next generation armored CAR-T cells with a drug inducible cytokine circuit. Theoretical and Natural Science,24,178-185.
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References

[1]. World Health Organization: WHO. (2022). Cancer. www.who.int. https://www.who.int/news-room/fact-sheets/detail/cancer

[2]. Maalej, K. M., Merhi, M., Inchakalody, V. P., Mestiri, S., Alam, M., Maccalli, C., Cherif, H., Uddin, S., Steinhoff, M., Marincola, F. M., & Dermime, S. (2023). CAR-cell therapy in the era of solid tumor treatment: current challenges and emerging therapeutic advances. Molecular cancer, 22(1), 20. https://doi.org/10.1186/s12943-023-01723-z

[3]. Hawkins, E. R., D’Souza, R. R., & Klampatsa, A. (2021). Armored CAR T-Cells: The Next Chapter in T-Cell Cancer Immunotherapy. Biologics : targets & therapy, 15, 95–105. https://doi.org/10.2147/BTT.S291768

[4]. Manhas, J., Edelstein, H. I., Leonard, J. N., & Morsut, L. (2022). The evolution of synthetic receptor systems. Nature chemical biology, 18(3), 244–255. https://doi.org/10.1038/s41589-021-00926-z

[5]. Flugel, C. L., Majzner, R. G., Krenciute, G., Dotti, G., Riddell, S. R., Wagner, D. L., & Abou-El-Enein, M. (2023). Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours. Nature reviews. Clinical oncology, 20(1), 49–62. https://doi.org/10.1038/s41571-022-00704-3

[6]. Li, H. S., Wong, N. M., Tague, E., Ngo, J. T., Khalil, A. S., & Wong, W. W. (2022). High-performance multiplex drug-gated CAR circuits. Cancer cell, 40(11), 1294–1305.e4. https://doi.org/10.1016/j.ccell.2022.08.008

[7]. Wu, Y., Liu, Y., Huang, Z., Wang, X., Jin, Z., Li, J., Limsakul, P., Zhu, L., Allen, M., Pan, Y., Bussell, R., Jacobson, A., Liu, T., Chien, S., & Wang, Y. (2021). Control of the activity of CAR-T cells within tumours via focused ultrasound. Nature biomedical engineering, 5(11), 1336–1347. https://doi.org/10.1038/s41551-021-00779-w

[8]. Allen, G. M., Frankel, N. W., Reddy, N. R., Bhargava, H. K., Yoshida, M. A., Stark, S. R., Purl, M., Lee, J., Yee, J. L., Yu, W., Li, A. W., Garcia, K. C., El-Samad, H., Roybal, K. T., Spitzer, M. H., & Lim, W. A. (2022). Synthetic cytokine circuits that drive T cells into immune-excluded tumors. Science (New York, N.Y.), 378(6625), eaba1624. https://doi.org/ 10.1126/science.aba1624

[9]. Smole, A., Benton, A., Poussin, M. A., Eiva, M. A., Mezzanotte, C., Camisa, B., Greco, B., Sharma, P., Minutolo, N. G., Gray, F., Bear, A. S., Baroja, M. L., Cummins, C., Xu, C., Sanvito, F., Goldgewicht, A. L., Blanchard, T., Rodriguez-Garcia, A., Klichinsky, M., Bonini, C., … Powell, D. J., Jr (2022). Expression of inducible factors reprograms CAR-T cells for enhanced function and safety. Cancer cell, 40(12), 1470–1487.e7. https://doi.org/10.1016/ j.ccell.2022.11.006

[10]. Yang, Z. J., Yu, Z. Y., Cai, Y. M., Du, R. R., & Cai, L. (2020). Engineering of an enhanced synthetic Notch receptor by reducing ligand-independent activation. Communications biology, 3(1), 116. https://doi.org/10.1038/s42003-020-0848-x

Cite this article

Drew,D.;Li,X.;Su,M.;Wang,Q. (2023). Next generation armored CAR-T cells with a drug inducible cytokine circuit. Theoretical and Natural Science,24,178-185.

Data availability

The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.

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About volume

Volume title: Proceedings of the 3rd International Conference on Biological Engineering and Medical Science

ISBN：978-1-83558-221-3(Print) / 978-1-83558-222-0(Online)
Editor：Alan Wang
Conference website: https://www.icbiomed.org/
Conference date: 2 September 2023
Series: Theoretical and Natural Science
Volume number: Vol.24
ISSN：2753-8818(Print) / 2753-8826(Online)

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References

[1]. World Health Organization: WHO. (2022). Cancer. www.who.int. https://www.who.int/news-room/fact-sheets/detail/cancer

[2]. Maalej, K. M., Merhi, M., Inchakalody, V. P., Mestiri, S., Alam, M., Maccalli, C., Cherif, H., Uddin, S., Steinhoff, M., Marincola, F. M., & Dermime, S. (2023). CAR-cell therapy in the era of solid tumor treatment: current challenges and emerging therapeutic advances. Molecular cancer, 22(1), 20. https://doi.org/10.1186/s12943-023-01723-z

[3]. Hawkins, E. R., D’Souza, R. R., & Klampatsa, A. (2021). Armored CAR T-Cells: The Next Chapter in T-Cell Cancer Immunotherapy. Biologics : targets & therapy, 15, 95–105. https://doi.org/10.2147/BTT.S291768

[4]. Manhas, J., Edelstein, H. I., Leonard, J. N., & Morsut, L. (2022). The evolution of synthetic receptor systems. Nature chemical biology, 18(3), 244–255. https://doi.org/10.1038/s41589-021-00926-z

[5]. Flugel, C. L., Majzner, R. G., Krenciute, G., Dotti, G., Riddell, S. R., Wagner, D. L., & Abou-El-Enein, M. (2023). Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours. Nature reviews. Clinical oncology, 20(1), 49–62. https://doi.org/10.1038/s41571-022-00704-3

[6]. Li, H. S., Wong, N. M., Tague, E., Ngo, J. T., Khalil, A. S., & Wong, W. W. (2022). High-performance multiplex drug-gated CAR circuits. Cancer cell, 40(11), 1294–1305.e4. https://doi.org/10.1016/j.ccell.2022.08.008

[7]. Wu, Y., Liu, Y., Huang, Z., Wang, X., Jin, Z., Li, J., Limsakul, P., Zhu, L., Allen, M., Pan, Y., Bussell, R., Jacobson, A., Liu, T., Chien, S., & Wang, Y. (2021). Control of the activity of CAR-T cells within tumours via focused ultrasound. Nature biomedical engineering, 5(11), 1336–1347. https://doi.org/10.1038/s41551-021-00779-w

[8]. Allen, G. M., Frankel, N. W., Reddy, N. R., Bhargava, H. K., Yoshida, M. A., Stark, S. R., Purl, M., Lee, J., Yee, J. L., Yu, W., Li, A. W., Garcia, K. C., El-Samad, H., Roybal, K. T., Spitzer, M. H., & Lim, W. A. (2022). Synthetic cytokine circuits that drive T cells into immune-excluded tumors. Science (New York, N.Y.), 378(6625), eaba1624. https://doi.org/ 10.1126/science.aba1624

[9]. Smole, A., Benton, A., Poussin, M. A., Eiva, M. A., Mezzanotte, C., Camisa, B., Greco, B., Sharma, P., Minutolo, N. G., Gray, F., Bear, A. S., Baroja, M. L., Cummins, C., Xu, C., Sanvito, F., Goldgewicht, A. L., Blanchard, T., Rodriguez-Garcia, A., Klichinsky, M., Bonini, C., … Powell, D. J., Jr (2022). Expression of inducible factors reprograms CAR-T cells for enhanced function and safety. Cancer cell, 40(12), 1470–1487.e7. https://doi.org/10.1016/ j.ccell.2022.11.006

[10]. Yang, Z. J., Yu, Z. Y., Cai, Y. M., Du, R. R., & Cai, L. (2020). Engineering of an enhanced synthetic Notch receptor by reducing ligand-independent activation. Communications biology, 3(1), 116. https://doi.org/10.1038/s42003-020-0848-x

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