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Cancer’s Living Cure: CAR t-cell Therapy


Image is courtesy of Cancer Treatment Centres of America.


What is CAR t-cell therapy?


In the past, treatment for cancer included surgery, chemotherapy, and radiation therapy. Recently, new treatments have emerged, including CAR (chimeric antigen receptor) t-cell therapy. This is a form of immunotherapy—a type of treatment that aids the immune system of patients with cancer. Immunotherapy improves the body’s ability to detect and kill cancer cells. It is also based on the concept that immune cells or antibodies can recognize and kill cancer cells.


Timeline of CAR t-cell therapy (Labiotech.eu).


How does CAR t-cell therapy work?


CAR t-cell therapy uses t-cells, a leukocyte (white blood cell) part of the immune system that focuses on specific foreign particles. There are two main types of t-cells: killer t-cells and helper t-cells. The immune system recognizes foreign substances in the body by finding antigens on the surface of these cells. On t-cells, there are receptors that attach to specific antigens like a lock and a key.


Previously, it took scientists several weeks to create a batch of CAR t-cells; however, with more advancements in the method of production, the time has been reduced to only 7 days. The process begins with the collection of t-cells from the blood of a cancer patient. This is done through apheresis, where blood is withdrawn from the body and blood components are separated. The remaining blood components are then re-introduced into the bloodstream.


The t-cells extracted from the blood are then changed in a lab by adding a man-made receptor. This receptor (the chimeric antigen receptor or CAR) helps the t-cells better identify cancer cell antigens. Each CAR is made to target a specific kind of cancer, such as leukemia or lymphoma.


Once the CAR t-cells have been made, they are given to the patient. Before an infusion, the patient is given chemotherapy, called lymphodepletion, to lower the number of other immune cells. CAR t-cells present in the patient’s blood will then multiply in number (about 1,000-10,000 fold), attacking the targeted cancer cells.


The process of CAR t-cell Therapy (Medical Xpress).


Current treatments and future improvements


Treatments that are FDA approved include Axicabtagene ciloleucel, Brexucabtagene autoleucel, Tisagenlecleucel, and Tocilizumab. These treatments are able to target some forms of lymphoma, a type of cancer that begins in the infection-fighting cells of the immune system, called lymphocytes. Many clinical trials of CAR t-cell therapy also exist for other types of cancer and solid tumors.


Several adjustments to CAR t-cell therapy are being tested for future use. This includes:

  • Using immune cells from healthy donors instead of from patients

  • Using CAR t-cell therapy to treat solid tumors

  • Using nanotechnology to create CAR t-cells inside the body

  • Using CRISPR/Cas9 to genetically engineer the t-cells

  • Expanding target to more forms of leukemia


Side effects of CAR t-cell therapy


Patients who receive the treatment will not experience the symptoms associated with chemotherapy, such as nausea, vomiting, or hair loss, making CAR t-cell therapy more appealing to cancer patients. However, there are some risks, although they are temporary and manageable with hospital care. A possible side effect is cytokine release syndrome. The CAR t-cells can initiate the release of cytokines, which trigger inflammation. This leads to flu-like symptoms, like fever, chills, and low blood pressure. Another side effect of the treatment is neurological difficulty due to neurotoxicity. Patients are subject to swelling, confusion, headaches, and even seizures. Lastly, there is a possibility that the CAR t-cells will kill off b-cells in the body. B-cells aid in fighting germs and bacteria, causing patients to have a higher risk of infection.


Image is courtesy of Oncology Nursing Society.


Efficacy


According to Michael Bishop, director of the University of Chicago Medicine’s cellular therapy program, CAR t-cell therapy has a success rate of 30-40% for remission. Remission means that the cancer has gotten smaller or the body shows no sign of cancer from tests, scans, and physical exams. In one trial, CAR t-cell therapy caused remission for 82% of the test subjects 3 months after the treatment was received. At 18 months, the overall survival rate was 70%. CAR t-cell therapy is so exciting since prior to the trial, patients were unresponsive to other treatments such as chemotherapy and bone marrow transplant.


Despite this, remissions are not always permanent. Although remission may be prevalent for some time, the cancer may return or the CAR t-cells may not last long in the body.


Recent News


Currently, CAR t-cell therapy is being developed for leukemia treatment, but this therapy is not as effective for solid tumors, such as neuroblastoma. In a study published by Nature Communications Journal, scientists at Children’s Hospital Los Angeles have developed a modified version of CAR t-cell therapy. This works to target neuroblastoma, showing potential for treating solid tumors. The team used a technology called synNotch, allowing scientists to target specific cancers precisely through a process called gating. In addition to this, the synNotch CAR t-cells are more metabolically stable since they are not always active. This is in contrast to normal CAR t-cells, which burn out after some time.


In another study, scientists at the Dana-Farber Cancer Institute have developed on-off switches that could regulate CAR t-cell activity. This is done through the drug, lenalidomide, and a technique called targeted protein degradation. While the on-off switches have only been tested in the lab and on live mice, the study has increased the potential for making CAR t-cell therapy safer, more reliable, and faster.



Article Author: Jennifer Law

Article Editors: Victoria Huang, Valerie Shirobokov