What are CAR T cells?
Chimeric antigen receptor (CAR) T cell therapy uses a patient's own T cells to fight cancer. T cells are a type of white blood cell that plays a key role in immune response. In CAR T cell therapy, a patient's T cells are genetically modified to better recognize and attack the cancer cells. The cells are reprogrammed to target a specific protein on the surface of cancer cells. This protein is usually found in large amounts on cancer cells but not healthy cells. Once infused back into the patient, these modified T cells can act as a "living drug" by directly killing cancer cells that express the targeted antigen.
How are CAR T cells generated?
The process to generate Car T Cell Therapy involves several steps. First, T cells are collected from the patient's blood through a process called leukapheresis, similar to donating plasma. These cells are then sent to a manufacturing facility where the gene for a customized CAR is inserted using a virus or donor cell nuclear transfer. The gene gives the T cells a new receptor on their surface which targets a specific protein on the patient's cancer cells. Once modified, the cells are grown and expanded in number. They undergo quality testing before being infused back into the patient. The entire manufacturing process usually takes 2-4 weeks. Once infused, the CAR T cells multiply inside the patient and circulate in the blood to detect and eliminate cancer cells.
Targeting CD19 for B cell malignancies
The most common target for CAR T cell therapy is CD19, a protein expressed on B cells and B cell cancers like leukemia and lymphoma. CD19-targeted CAR T cells have shown impressive results against B cell cancers where other treatments have failed. In clinical trials, over 80% of patients with certain types of acute lymphoblastic leukemia (ALL) achieved complete remission with CD19 CAR T cell therapy. Durable remissions were also seen in over 50% of patients with diffuse large B cell lymphoma (DLBCL) who did not respond to chemotherapy. CD19 is an ideal target as it is expressed throughout the course of B cell cancers but not on other non-cancerous tissues, allowing CAR T cells to effectively kill cancer cells while sparing healthy cells.
Managing side effects of CAR T cell therapy
While highly effective, CAR T cell therapy can sometimes cause severe side effects as a result of immune overactivation. Common side effects seen in up to 90% of patients include fever, headache, nausea, vomiting, and low blood pressure which usually occur within 1-2 weeks of treatment as CAR T cells rapidly multiply in response to cancer. More serious side effects like cytokine release syndrome (CRS) and neurotoxicity have also been reported. CRS occurs due to high levels of inflammatory molecules released as T cells attack cancer, causing symptoms ranging from mild fever to life-threatening low blood pressure and respiratory problems. Steroids like dexamethasone are typically used to quickly alleviate CRS if it develops. Another potential side effect called immune effector cell-associated neurotoxicity syndrome (ICANS) can cause confusion, drowsiness, and seizures. Careful screening, risk assessments, and plans for managing side effects are essential components of CAR T cell therapy. With improving conditioning regimens and supportive care, side effect profiles are continuously getting better managed.
Advancing CAR T cell therapy for solid tumors
While CAR T cell therapy so far has shown remarkable results against certain types of leukemia and lymphoma, developing effective CAR T cell treatments for solid tumors poses tremendous challenges. Solid tumors have more heterogeneous antigens which make it difficult for CAR T cells to recognize and eliminate them. They also create a hostile microenvironment deficient in nutrients and enriched in immunosuppressive factors which impair T cell function and persistence. Advances are now focused on overcoming these obstacles through co-targeting multiple tumor antigens, combination therapies, optimizing conditioning regimens, cytokine support, and developing innovative next-generation CARs. Areas of active research also include equipping CAR T cells with abilities like enhanced trafficking, resistance to exhaustion and dependence on immunosuppressive factors. With these ongoing improvements, CAR T cell therapy holds promise to expand its reach beyond blood cancers to revolutionize the treatment of several solid tumors like lung cancer, breast cancer, glioblastoma in the future.
Managing long term efficacy and safety
As CAR T cell therapy moves past early clinical trials, longer term efficacy and safety data is still emerging. For responders who achieve remission, the key challenge is sustaining the effects of a single dose of CAR T cells for extended durations. Median duration of response has varied from 6-12 months with presently available CD19 CAR T cell therapies. However, some patients show prolonged remissions for several years. Managing tumor relapse and monitoring for late effects remain important ongoing considerations. Developing novel strategies to enhance long term CAR T cell persistence is an active area of clinical research. Ensuring robust expansion and durable activity of infused cells remains essential. At the same time, continuous vigilance is required for late toxicities like B cell aplasia or second malignancies which fortunately remain rare. As patient outcomes mature, understanding and addressing long term efficacy as well as any safety concerns will shape the future of this revolutionary cancer treatment approach.
CAR T cell therapy has emerged as a promising new approach that harnesses the power of a patient's own immune system to combat cancer. Targeting CD19 has achieved spectacular results in certain blood cancers where other options are limited. Ongoing progress addresses challenges in solid tumors and optimizes engineering to bolster CAR T cell potency, persistence and safety. With continuous improvements from ongoing research, CAR T cell therapy carries immense potential to transform treatment across numerous cancers. While it still remains an investigational advanced therapy, early clinical success highlights CAR T cells as one of the most innovative advances so far in the quest to develop more effective personalized cancer immunotherapies.
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