Research results published in Nature this month demonstrate that chimeric antigen receptor (CAR) T-cell therapy, which uses engineered T-cells to target cancer, held leukemia at bay in two patients for at least 10 years. The patients — who both had chronic lymphocytic leukemia (CLL) — received the experimental therapy in 2010 and remained cancer-free for 10 years. One patient died in early 2021 from COVID-19 complications. The other is considered cured of cancer.
CAR T-cell therapy modifies a person’s T-cells to recognize and attack specific proteins on cancer cells. The immunotherapy starts with removing T-cells from blood taken from a person with cancer. The T-cells are isolated and genetically modified so that they produce proteins — CARs — that will recognize and attach to the targeted cancer cells. The modified cells are reinfused into the same person’s body, where they seek out and destroy cancer cells.
Shifting T-Cell Identities
The new research showed that the patients continued to produce modified T-cells over an extended time, which kept the leukemia in remission. Interestingly, it also showed that the nature of the T-cell populations changed over the course of the study. The patients’ immune systems initially responded to the therapy by pumping out powerful but typically rare CD8+ T-cells, also called killer T-cells. Over time, however, CD4+ T-cells dominated. Throughout the years, these cells continued to proliferate, and the research showed that they had the ability to attack leukemia cells. The fact that CAR T-cells can survive and thrive in the body over an extended period of time is the key to the treatment’s efficacy.
“We can now conclude that CAR T-cells can actually cure patients with leukemia,” said one of the study’s co-leaders, Carl June, professor of Pathology and Laboratory Medicine at the University of Pennsylvania.
Promising Last-Resort Treatment
The therapy, marketed as Kymriah® by Novartis, received Food and Drug Administration approval in 2017 for the treatment of acute B-cell lymphoblastic leukemia. It was also approved for patients with certain types of lymphoma in 2018. Although the FDA has approved four other CAR T-cell therapies — Abecma®, Breyanzi®, Tecartus™ and Yescarta®— there are no CAR T-cell therapies currently approved for treating CLL.
The treatment is costly and difficult to produce due to the complex manufacturing process and rigorous safety and efficacy criteria. Therefore, it is used as a last resort treatment when all other options have failed. Unfortunately, not all patients have long-lasting results. Initially, only 25 to 35 percent of treatment recipients with CLL achieved complete remission. This rate has improved over time as scientists have refined the approach. Long-term tracking of treatment outcomes may help explain the factors most important to obtaining positive results.
Other Potential Disease Targets
This approach may someday be applied to treating other diseases. Currently, researchers are investigating CAR T-cell therapy for solid tumors, such as prostate tumors and the brain cancer, glioblastoma. In January, researchers published promising results from an attempt to use CAR T-cell therapy to destroy scar tissue in the heart, indicating that this approach could potentially be used to treat cardiac fibrosis.
“The potential impact of CAR T is tremendous,” said Nirali Shah, a pediatric hematologist at the National Cancer Institute in Bethesda, Maryland. This study “gives you a proof-of-concept about the safety of having long-term persistence and integration of the T-cells into your body.”
Joseph Melenhorst, a professor of Pathology and Laboratory Medicine at the University of Pennsylvania who co-led the study, agreed. “This long-term remission is remarkable and witnessing patients living cancer-free is a testament to the tremendous potency of this ‘living drug’ that works effectively against cancer cells. Witnessing our patients respond well to this innovative cellular therapy makes all of our efforts so worthwhile.”
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