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CAR-T Immunotherapy: New Treatment, New Hope

For decades, the list of standard treatments for many blood cancers has remained short and largely unchanged. But now there is a new entry on the list. If chemotherapy and a bone marrow transplant fail to stop the cancer, doctors can harness a type of personalized immunotherapy that trains a person’s own immune system to attack cancer cells.

At the heart of the new therapy are the immune system’s T cells, which typically fight off disease. In patients with cancer, however, these cells lose the ability to recognize and attack cancer cells. In this new treatment, a patient’s  T cells are extracted and genetically altered — or supercharged — so that they specifically home in on the type of cell affected by the cancer. These modified T cells have been dubbed CAR-T cells, or chimeric antigen receptor T cells. Once a CAR-T cell finds its target, it behaves as any T cell should, triggering a chain of reactions that destroys the target cell.

If cancerous cells find ways to fly under the radar of immune surveillance, the new therapy renders these cancers visible again. “The immune system can’t always see cancer cells as threats — the T cells are sometimes blind to them,” says John DiPersio, MD, PhD, director of the Division of Oncology at Washington University School of Medicine and deputy director of Siteman Cancer Center. “By modifying these T cells, we tell them what to look for.

Now they can go right to the leukemia or lymphoma  and eliminate the cancerous cells.” DiPersio is also the director and scientific co-director of the Center for Gene & Cellular Immunotherapy.

CAR-T cells are often referred to as a living drug because they expand their numbers dramatically once in the bloodstream. And like other T cells, they remember what their targets look like, sometimes long after the offending cells have been eradicated. While long-term data is still being gathered, there is evidence that some CAR-T cells may maintain their active surveillance and ramp up again in response to cancer recurrence. The fact that CAR-T cells can be given different programming, locking them on to different cell surface features, suggests the strategy could be expanded to other cancers.

But because the therapy induces a heightened immune response, there can be a range of side effects, from fever and shortness of breath to kidney failure and seizures. Many of the side effects are manageable, but some are severe and a few can be life-threatening, which is why the first centers selected to administer the new therapy are those with extensive expertise in treating blood cancers. That expertise includes long histories of success in bone marrow transplantation and management of the sometimes severe side effects of that similarly intensive, but standard, therapy for many blood cancers. Siteman Cancer Center was among the first centers selected to  offer CAR-T therapy.

“The toxicities of bone marrow transplantation and CAR-T cells are completely different, but we are well-equipped to manage both,” DiPersio says. “We have approved therapies we can give to counter one of the primary side effects of CAR-T cells called cytokine release syndrome, which causes symptoms like low blood pressure, high fevers, chills, swelling and kidney failure. Some patients who receive CAR-T therapies also can experience life-threatening neurologic toxicities that we are still working to understand.”

The first cancers to be treated with CAR-T include certain types of large B-cell lymphomas in adults and acute lymphoblastic leukemia, or ALL, in children. Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma in adults. Such cancers in children and adults are characterized by the production of too many B cells, a type of white blood cell that is also a part of the immune system. CAR-T cell therapy for pediatric ALL, called Kymriah, was approved by the FDA at the end of August 2017 and is available through Siteman Kids at St. Louis Children’s Hospital.

CAR-T clinical trials have shown what doctors have called remarkable remission rates among children with ALL and adults with lymphomas and multiple myeloma. In patients whose disease has not responded to standard therapies or has relapsed, CAR-T has achieved from 40 to 80 percent remission rates. Some patients have remained in remission for several years. Washington University doctors and researchers were involved in clinical trials that led to the FDA approval of the new CAR-T cell therapy, called Yescarta, and are working to develop other immunotherapies that attack cancer.

Physician-scientists at Siteman Cancer Center are evaluating CAR-T cell therapy in a clinical trial for leukemia and soon will begin a trial in patients with multiple myeloma, another type of blood cancer, and with patients with ovarian cancer. Additional clinical trials involving therapies similar to CAR-T are also available for patients with sarcoma, a cancer of bones and connective tissue; lung cancer; and melanoma, a skin cancer.

Currently, CAR-T therapy for adults with non-Hodgkin lymphoma is available only to people whose cancer has not responded to standard treatments, including chemotherapy and bone marrow transplantation. 

“This is the beginning of a new era of cancer therapy,” says Armin Ghobadi, MD, an oncologist at Siteman Cancer Center and the clinical director of the Center for Gene & Cellular Immunotherapy. “With CAR-T cell therapy, we can take patients’ own cells and turn them into a powerful weapon to attack cancer. It’s a highly personalized, innovative therapy and one we hope also will prove to  be effective against many different types of cancer.”

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