What are CAR T Cells?
Chimeric antigen receptor T cell (CAR-T) therapy utilizes the body's own immune system to fight cancer. In CAR-T therapy, a patient's T cells, a type of immune system cells, are changed in the lab to specifically target and destroy cancer cells. The T cells are collected from a patient through a process called leukopheresis. The genes of the T cells are then altered in the lab so that they produce chimeric antigen receptors (CARs) on their surface. These CARs are engineered to recognize a specific protein, called an antigen, that is found on the outside of the patient's cancer cells. Once infused back into the patient, the altered CAR T cells can zero in on and wipe out the cancer.
How does CAR T Therapy Work?
In Car T Cell Therapy, scientists first identify a protein that is specific to the patient’s cancer. For example, CD19 is an antigen that is often used as a target antigen in CAR-T therapies for blood cancers like leukemia and lymphoma. Once this target antigen is selected, T cells are collected from the patient and genetically modified in the lab to add the gene for a chimeric antigen receptor (CAR). This CAR contains an antibody-derived binding domain that is engineered to specifically recognize the target antigen on the patient’s cancer cells. In addition, the CAR contains other domains that activate and stimulate the T cells upon binding to the antigen. When these modified CAR T cells are infused back into the patient, they can migrate through the body to seek out and destroy any cancer cells that express the target antigen on their surface. By redirecting the patient’s own T cells to recognize and kill cancerous cells, CAR-T therapy shows great promise as a targeted treatment.
Clinical Trials and Patient Outcomes
CAR-T cell therapy has shown great promise in clinical trials, particularly for blood cancers like acute lymphoblastic leukemia and non-Hodgkin lymphoma. In 2017, both Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel) were approved by the FDA to treat certain types of lymphoma and leukemia. Results from these pivotal clinical trials showed very high response rates, with over 80% of leukemia patients achieving complete remission after receiving CAR-T therapy. Long-term follow up has found some patients experiencing sustained remissions for years after a single treatment. However, it is worth noting that clinical trials to date have primarily enrolled patients who have already exhausted standard therapies and have highly aggressive disease. CAR-T therapy also comes with considerable risks of severe side effects due to the intensive immune response that it triggers. Some of the most significant risks seen in trials include a potentially life-threatening cytokine release syndrome and neurotoxicity. Careful patient selection and management of side effects remain important aspects of safely delivering this powerful new therapy in the real world.
Expanding Applications of CAR T Cells
Initial CAR-T therapies were developed to target the CD19 antigen in blood cancers. However, researchers are now working on applying this approach for solid tumors as well. Some new areas of focus include targeting the PSMA antigen for prostate cancer, EGFRvIII for glioblastoma, and HER2 for breast and other cancers. Delivery and persistence of CAR T cells in the solid tumor microenvironment poses unique challenges compared to blood cancers. Ongoing research is exploring ways to address hurdles like physical barriers preventing T cell infiltration, an immunosuppressive tumor environment, and the need for improved persistency to successfully eradicate solid tumor sites. Other strategies under investigation include developing next generation CAR-T cells with added co-stimulatory domains for increased potency, generating allogeneic "off-the-shelf" CAR-T products, and combining CAR-T therapy with checkpoint inhibitors or other therapeutic agents. As the science advances, it is hoped that CAR-T cell therapy can be expanded for many cancer types.
Improving Safety and Availability
While clinical trials indicate CAR-T cell therapy can provide remarkable outcomes in certain hematologic malignancies, broader use will require addressing significant treatment challenges. Due to the complexity of manufacturing living cell therapies, current CAR-T products are associated with high costs, averaging over $373,000 per treatment. In addition, therapy must be delivered rapidly via certified cancer treatment centers, limiting availability. Risks of life-threatening adverse effects also underscore the need for careful safety management. Ongoing advances aim to streamline manufacturing, improve toxicity profile, and develop standardized regimens that enhance consistent delivery. The use of universal allogeneic CAR-T or gene therapy approaches may also allow "off-the-shelf" availability in the future. As CAR-T research accelerates, addressing barriers impacting real-world safety, convenience and costs will be vital to fulfill the promise of bringing personalized cell therapies to all patients who can benefit.
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