Introduction to Genetically Engineered T Cells
An introduction to genetic modulation of immune cells by genetically engineered T cells
Introduction
Cellular immunotherapy uses the cells of the immune system to fight against diseases such as cancer and infections1–3
As a gene therapy approach, cellular immunotherapy involves genetically engineering immune cells, such as T cells, to enhance their ability to attack diseased cells1,2
T cells are particularly suitable due to their unique4:
This allows for4:
Examples of cellular immunotherapy using gene therapy approaches include chimeric antigen receptor (CAR) T-cell therapy (CAR-T) and T-cell receptor (TCR) therapy5
Both CAR-T and TCR therapies are forms of personalized immunotherapy that use the patient’s own immune system to fight against certain types of cancer5
In both therapies, the expression of the new or modified receptor enables T cells to target specific cell antigens5
Because T-cell-based therapies offer a systematic gene therapy approach, they are of considerable interest for the treatment of cancer and metastasis6
CAR-T has demonstrated remarkable results, particularly for the treatment of hematologic malignancies5,7
Other technologies such as genome editing are being investigated as a modality to modify T cells5,8
Engineered T-Cell Therapy: Production Process
The general production process for engineered T-cell therapy can be divided into four steps5
Engineered T-cell therapy starts by collecting and isolating T cells from the patient, with a process known as leukapheresis (a type of apheresis). The rest of the blood is then transfused back into the patient5,9,10
Isolated T cells are transduced by viral (usually via lentiviral or retroviral vectors) or non-viral vectors to express specific CARs/TCRs5,10
- Genetically modified T cells are grown ex vivo in the presence of cytokines, which promote the stimulation of a large number of T cells into modified T cells5
- The expanded population of modified T cells can be frozen for future administration5
- Following amplification and quality control, the engineered T cells are transfused back into the patient’s body5
- Patients are given preconditioning chemotherapy before administration5
Beyond CAR-T and TCR Therapy
Other gene modifications are being investigated and aim to further enhance the activity of
Forcible expression of chemokine receptors on T cells would enable their migration to tumor sites11
Cytokine expression by T cells in an autocrine fashion would enhance T-cell survival and function11
Expression of checkpoint inhibitors that bind to checkpoint receptors on T cells activate T cells, which results in the killing of tumor cells11
A dominant-negative receptor would help to block the immunosuppressive effects of cytokines (such as transforming growth factor β) secreted by tumor cells that inhibit the function of host immune cells and induce metastasis11
Graph adapted from Patel S, et al. 201911.
References
- Li D, et al. Signal Transduct Target Ther 2019;4:35.
- Perica K, et al. Rambam Maimonides Med J 2015;6(1):e0004.
- Seif M, et al. Front Immunol 2019;10:2711.
- Johnson JM, Tuohy VK. Targeting antigen-specific T cells for gene therapy of autoimmune disease. In: Madame Curie Bioscience Database [Internet]. Austin, TX: Landes Bioscience, 2013.
- Zhao L, Cao YJ. Front Immunol 2019;10:2250.
- Anguela XM, High KA. Annu Rev Med 2019;70:273–288.
- Srivastava S, Riddell SR. J Immunol 2018;200(2):459–468.
- Liu J, et al. Front Immunol 2019;10:456.
- Cleveland Clinic. CAR T-Cell Therapy: Procedure Details. Available at: https://my.clevelandclinic.org/health/treatments/17726-car-t-cell-therapy/procedure-details. Accessed December 7, 2020.
- Zhao Z, et al. Acta Pharm Sin B 2018;8(4):539–551.
- Patel S, et al. Front Oncol 2019;9:196.
