New CAR-T therapy achieved complete remission in 70% of aggressive cancer patients

CAR-T cell therapy has revolutionized the treatment of relapsed and refractory B-acute lymphoblastic leukemia (B-ALL), with remission rates reaching as high as 90%. This therapy modifies a patient’s T cells to recognize and destroy cancer cells.

However, many patients experience relapse due to either the loss of targeted cancer markers or insufficient CAR-T cell persistence. Scientists have been working to overcome these challenges, and a new approach may hold the key to more effective and longer-lasting treatments.

Despite impressive initial remission rates, relapses remain a major obstacle. Some cancer cells survive by reducing the expression of the targeted antigen, making them harder for CAR-T cells to detect. Others evade therapy by switching cell lineages, effectively disguising themselves.

For those who relapse with cancer cells that no longer express CD19—the primary target of traditional CAR-T therapy—treatment options are extremely limited. Researchers turned to an alternative marker, CD22, in an effort to expand therapeutic targets.

CD22-directed CAR-T cells showed promise, achieving complete remission in about 70% of patients who had previously undergone CD19-based treatment. However, most eventually relapsed due to cancer cells expressing CD22 at levels too low for CAR-T cells to detect effectively.

Similar challenges have been observed with other CAR-T therapies targeting different antigens, such as CD19, CD20, and ALK. This suggests that second-generation CAR-T cells struggle against cancer cells with low antigen expression.

Researchers at the University of Colorado Anschutz Medical Campus have developed a breakthrough therapy known as ALA-CART (Adjunctive LAT-Activating CAR-T). Unlike previous CAR-T therapies, this approach enhances how T cells process signals, making them more effective at targeting cancer cells even when antigen levels are low.

The study was published in the journal  Cancer Cell.

“ALA-CART improves the ability of CAR-T cells to detect and attack resistant cancer cells more effectively. This could lead to longer-lasting results, even when other treatments have failed,” said M. Eric Kohler, MD, PhD, a leading researcher in the study.

This new technology works by enhancing the activation of a key protein complex called the T cell signalosome, which regulates immune response. Standard CAR-T cells often suffer from suboptimal signaling when encountering antigen-low cells, reducing their effectiveness. ALA-CART includes a second receptor designed to improve this signaling process, restoring the T cells’ ability to attack even the most elusive cancer cells.

The impact of ALA-CART extends beyond just overcoming antigen-low escape. The improved signaling not only boosts the immune response but also enhances CAR-T cell persistence, increasing their longevity in the body. In preclinical trials using specialized mouse models, ALA-CART cells demonstrated stronger and more durable responses to acute lymphoblastic leukemia (ALL) compared to traditional CAR-T therapies.

“This next-generation approach optimizes CAR-T cells to more effectively eliminate cancer cells, including those that have been able to hide from traditional CAR-T cells,” said Catherine Danis, PhD, lead author and postdoctoral fellow at the University of Colorado School of Medicine.

The researchers believe that ALA-CART could also help reduce some of the common side effects associated with CAR-T therapy, such as excessive immune activation. Since the new design allows for more precise targeting, it may decrease the risk of severe inflammatory reactions, making it a potentially safer treatment option.

With these promising preclinical results, researchers are preparing for human trials to assess ALA-CART’s safety and effectiveness. If successful, this therapy could offer a new lifeline for patients who relapse after traditional CAR-T treatment.

“When you look back, it’s easy to see how revolutionary CAR-T cells have been. But, for many patients, this therapy isn’t enough. And stepping back, you realize that we have been driving these CAR-T cells with the same basic design for the last 15 years,” Kohler said. “When we began this project, we wanted to understand why this design allowed certain leukemia cells to escape therapy. Once we understood that, we knew how to design our ALA-CART cells.”

The research team hopes to begin clinical trials within the next two years. Meanwhile, they are also testing ALA-CART on other difficult-to-treat cancers, such as acute myeloid leukemia, multiple myeloma, and solid tumors.

“This marks a major shift in cancer immunotherapy, offering a groundbreaking innovation that could eventually improve survival and quality of life for patients with some of the most difficult-to-treat cancers,” Danis said.

If ALA-CART proves successful in clinical trials, it could significantly enhance cancer treatment, making CAR-T therapy more effective for a broader range of patients. This advancement may not only extend survival but also improve the overall quality of life for those battling the most challenging forms of cancer.

Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.

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