While CAR T-cell therapies have transformed the treatment landscape for specific cancers, a notable drawback remains: many patients experience relapse after achieving full remission. Researchers have now detailed a promising technique that could address this challenge.
The method, highlighted in a recent article in Nature Biotechnology, enhances the activity and longevity of CAR T cells within the body, allowing them to remain vigilant until all cancer cells are eliminated. This approach introduces a new therapeutic platform termed CAR-Enhancer (CAR-E) that not only boosts CAR T cells’ persistence but also helps them to recognize the cancer, enabling them to respond effectively if the cancer returns.
In studies involving laboratory models derived from patient cancer cells and other research, the CAR-Enhancer treatment successfully eliminated all cancer cells, paving the way for upcoming clinical trials in human patients. Researchers aim to initiate the first trial soon.
“CAR T-cell therapies have marked a significant breakthrough for B-cell cancers such as leukemias and lymphomas as well as multiple myeloma,” stated the study’s lead author, Mohammad Rashidian, PhD, from Dana-Farber. “In cases of myeloma, nearly all patients initially respond well to CAR T-cell therapies; however, almost all patients experience a relapse, often within one to two years of treatment, coinciding with the loss of CAR T cells in the bloodstream.”
“Most research aimed at tackling this issue has concentrated on modifying the CAR T cells themselves—such as altering or removing genes to keep the cells active for extended periods,” he noted. “While these methods show promise, they have not yet demonstrated significant effectiveness in clinical settings. We approached the problem from a different angle.”
Rather than altering the internal dynamics of CAR T cells, Rashidian and his team devised a strategy that works externally by delivering a molecule that prolongs the cells’ functionality and induces memory formation. This novel ‘platform’ is distinctly unlike any previous medical treatment.
CAR T cells are genetically modified versions of a patient’s own immune T cells aimed at combating cancer. The process involves extracting several million T cells from the patient’s blood and genetically engineering them to express a chimeric antigen receptor (CAR) on their surface, designed to recognize specific markers found on tumor cells. These CAR T cells are then expanded in the lab to reach hundreds of millions before being reinfused into the patient, where they target the cancer cells.
“This immune assault leads to the destruction of nearly all cancer cells, but a few may survive,” Rashidian elaborates. “The CAR T cells are effector cells created to eliminate cancer; when there are no targets left, they assume their job is done and vanish. Leftover tumor cells can give rise to a cancer comeback.”
To enhance the durability of CAR T cells and provide them with long-term memory, the researchers developed a groundbreaking therapeutic agent known as the CAR-E platform. This involves a weakened form of the immune signaling molecule interleukin-2 (IL-2) attached to the very antigen that CAR targets.
“IL-2 is potent in promoting T cell activation and proliferation, but it can also be quite toxic for patients,” Rashidian explained. “Therefore, we used a significantly weaker variant. While it does not impact normal T cells, it effectively stimulates CAR T cells when directed at them.”
This targeted approach is achieved by attaching IL-2 to the B-cell maturation antigen (BCMA), which is what the CAR targets in myeloma therapies.
“On its own, weak IL-2 and the BCMA antigen do not provoke CAR T cells, but when combined, they produce results that exceed our expectations,” noted Taha Rakhshandehroo, PhD, a co-author of the study.
The CAR-E therapy not only encourages CAR T cells to proliferate but also promotes diversity among them, creating various types with distinct functionalities. “It produced a full spectrum of T cells essential for a robust immune response to cancer, including effector T cells and various memory T cell types,” Rashidian stated.
In both laboratory studies of myeloma cells and animal models, CAR-E therapy consistently led to the complete destruction of tumor cells—effectively erasing any traces of the cancer.
Moreover, researchers found that the long-lasting CAR T cells created via this therapy could be reactivated with additional doses of CAR-E. This implies that patients experiencing a relapse after CAR T-cell treatment might be effectively managed with subsequent CAR-E therapies. Additionally, CAR-E may offer the possibility of using fewer CAR T cells than currently required, as the current model necessitates multiplying the cells into the hundreds of millions—a lengthy, costly, and resource-intensive process that often leads to side effects like cytokine release syndrome. The implementation of CAR-E could potentially allow for the direct infusion of CAR T cells followed by CAR-E treatment, thereby skipping the extensive amplification process.
“In our animal studies, mice infused with a minimal number of CAR T cells couldn’t eliminate cancer. However, when treated with CAR-E, those CAR T cells expanded and successfully cleared the cancer,” Rashidian shared.
The primary objective of an upcoming clinical trial for CAR-E therapy will be to ensure safety and identify the optimal dosage and treatment schedule. They anticipate that the CAR-E treatment would begin about a month after CAR T-cell infusion, consisting of a weekly administration for three to four weeks.
“What’s particularly exciting about this therapy is its seamless integration into the existing CAR T-cell treatment regimen,” Rakhshandehroo stated. “It’s a remarkable solution to the issue of CAR T-cell depletion, and we’re enthusiastic about beginning clinical trials.”
This research was supported by the Dana-Farber Cancer Institute Innovation Research Fund Award, the Parker Institute for Cancer Immunotherapy, and a Blavatnik Therapeutics Challenge Award.
