by What are CAR T Cells?
The Basics of Chimeric Antigen Receptor T-Cell Therapy
Chimeric antigen receptor T-cell (CAR T-cell) therapy is an innovative new approach to cancer treatment that utilizes a patient’s own immune system cells, known as T cells, to fight cancer. In CAR T-cell therapy, T cells are collected from a patient through a process called leukapheresis. The T cells are then engineered by adding a chimeric antigen receptor (CAR) to their surface through genetic modification. This CAR directs the T cells to target and attack cancer cells that express a specific protein on their surface. Once infused back into the patient, the CAR T cells can multiply and induce an anti-tumor response.
How Do CAR T Cells Work?
Targeting Specific Cancer Antigens
CARs are designed to target antigen molecules, commonly called tumor antigens, that are found on the surface of cancer cells but not on normal cells. The most common tumor antigens targeted in CAR T-Cell clinical trials include CD19, CD20, and HER2/neu. When infused back into the patient, the CAR T cells detect the tumor antigen displayed by cancer cells and become activated. Once switched on, the CAR T cells start proliferating rapidly and releasing cytotoxic molecules that destroy the cancer cells. The goal is for the engineered CAR T cells to multiply in number and eliminate the cancer without harming normal tissues in the body that do not express the targeted antigen.
Results from Pivotal Clinical Trials
Promising Outcomes for Certain Hematologic Malignancies
Since the first CAR T-cell therapy was approved by the FDA in 2017 for children and young adults with B-cell acute lymphoblastic leukemia (ALL), clinical trials have shown very promising results for CAR T-cell therapy, especially in treating certain blood cancers. Early phase studies reported high complete remission rates of 70-90% in patients with relapsed or refractory B-cell leukemias and lymphomas using CD19-targeted CAR T cells. Pivotal phase II trials in adults with relapsed/refractory large B-cell lymphoma also found response rates of 40-50% with durable responses. These promising outcomes led to FDA approvals of two CD19-targeted CAR T-cell therapies for certain types of leukemia and lymphoma. However, results have been more modest so far in testing CAR T cells against solid tumors. Extensive ongoing research continues to advance CAR T-cell therapy and develop new targets.
Side Effects and Safety Considerations
Managing Life-Threatening Toxicities
While CAR T-cell therapy has shown impressive results in hematologic malignancies, it also comes with substantial risks due to potential life-threatening side effects, especially during the first few weeks post-infusion. CAR T-cell therapy can cause an immune overresponse called cytokine release syndrome in which high levels of cytokines are released systemically. Symptoms range from mild flu-like symptoms to severe systemic inflammatory response requiring intensive care. Neurologic toxicities from CAR T-cell therapy include confusion, altered mental status, seizures, and neurologic dysfunction. Careful patient selection and developing strategies for risk mitigation and timely intervention with tocilizumab and corticosteroids when side effects occur have helped manage these toxicities and reduce treatment-related mortality. Close patient monitoring is still needed with CAR T-cell therapy.
Optimizing Therapies and Expanding Applications
There is an active effort ongoing in cancer immunotherapy research to optimize CAR T-cell therapy and expand its applications. Areas of ongoing investigation include developing next-generation CAR designs with built-in safety switches and combination strategies, exploring new tumor antigens beyond CD19, incorporating dendritic cell vaccines to boost CAR T-cell function, and identifying predictive biomarkers. Scientists are also trying to make the manufacturing process more widely accessible and affordable. Early phase clinical trials are testing CAR T-cell therapy against new tumor types including solid tumors. Advances in gene editing with CRISPR/Cas9 are also being explored to insert additional genes in CAR T cells to improve their potency and persistence. With further research and development, CAR T-cell therapy holds promise to transform cancer therapy in the years to come.
