CAR T-cell

Chimeric Antigen Receptor (CAR) modified T-cells is one of the next-generation technologies in oncologic medicine. The CAR T-cells rely on the concept of the immune system to treat cancers using genetically modified T-lymphocytes. Several clinical trials have been conducted in the CAR T cell field, with the first FDA-approved CAR T-cell therapy introduced in 2017 in the United States.1 The technology serves as the treatment for patients with relapsed or refractory (R/R) blood cancers such as acute lymphoid leukemia (ALL) and diffuse large B-cell non-Hodgkin lymphoma (DLBCL) who fail the conventional medicines.

The CAR T-cell therapy demonstrates promising efficacy with the complete response event rate of 77% (95% CI, 63-87%) in R/R ALL and 46% (95% CI, 38-54%) in R/R DLBCL.2,3 However, life-threatening adverse events after CAR T-cell infusion such as cytokine release syndrome, neurologic and neurologic toxicity could occur.2 Due to the possible serious side effect, the standard of care and monitoring needs to be ensured during the treatment.

1 FDA approval brings first gene therapy to the United States https://www.fda.gov/news-events/press-announcements/fda-approval-brings-first-gene-therapy-united-states Published August 2017.
2 Grigor, E.J., Fergusson, D., Kekre, N., Montroy, J., Atkins, H., Seftel, M.D., Daugaard, M., Presseau, J., Thavorn, K., Hutton, B. and Holt, R.A., 2019. Risks and benefits of chimeric antigen receptor T-cell (CAR-T) therapy in cancer: a systematic review and meta-analysis. Transfusion medicine reviews, 33(2), pp.98-110.
3 Al-Mansour M, Al-Foheidi M, Ibrahim E. Efficacy and safety of second-generation CAR T-cell therapy in diffuse large B-cell lymphoma: A meta-analysis. Mol Clin Oncol. 2020;13(4):33. doi:10.3892/mco.2020.2103

Process for CAR T-cells Therapy

At the clinical site, Leukapheresis was performed to separate white blood cells enriched blood from patient or donor. The separated white blood cells are transported to a manufacturing facility via cold chain transport.
Isolation, Activation, and Transduction
At the facility, T-cells are isolated from white blood cells and are activated. Viral vectors are used to genetically modify T-cells, resulting in an expression of specific receptors toward targeted cancer cells. The genetically engineered T-cells are called CAR T-cells.
CAR T-cells are expanded to suitable cell numbers. Release testing is checked before release the product to the destined hospital.
CAR T-cell Infusion
CAR T-cell product is shipped back to the clinical site for infusion into the patients. The CAR T-cells will specifically bind with the targeted cancer cells and induce destruction of the cancer cells via an immune process.

An 11-year-old boy with refractory, multiply relapsed acute lymphoid leukemia.

The boy was diagnosed with B-cell ALL at 3 years of age. He was non-responsive to several rounds of chemotherapy protocols. At 11-year-old, he developed a central nervous system (CNS) relapse with brain tumor. Target therapy-based regimen, intrathecal chemotherapy, brain, and spinal cord irradiation were given, resulting in a new complete remission. Six months later, he again had systemic bone marrow relapse. He was enrolled in compassionate clinical protocol at Ramathibodhi hospital, Bangkok, and was given haploidentical CD19 CAR T-cells donated from his mother. With no serious side effect, the patient remains ongoing complete remission 10+ after the treatment.

Reference: Prasongtanakij, S, Anurathapan, U, Vanichapol, T, et al. Production and characterization of haploidentical CD19 CAR T‐cells: Validated to induce a continuous complete remission in a patient with relapsed refractory B‐cell ALL. Asia-Pac J Clin Oncol. 2020; 18. https://doi.org/10.1111/ajco.13474