For over a decade, CAR-T cell therapy has transformed cancer treatment, offering a personalized approach by genetically engineering a patient’s immune cells to target cancer. But for some patients, these cells lose their potency, allowing cancer to relapse. Now, researchers at the University of Colorado Anschutz Medical Campus have unveiled a next-generation upgrade—one that may overcome these limitations and make CAR-T therapy more effective and longer-lasting.

Their study, published in Cancer Cell, introduces ALA-CART (Adjunctive LAT-Activating CAR-T cells), a breakthrough modification that enhances CAR-T cells’ ability to seek out and destroy even the most elusive cancer cells.

“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.

Upgrading CAR-T Cells for Greater Precision and Persistence

CAR-T cell therapy involves extracting a patient’s T cells, engineering them to recognize and attack cancer cells, and reinfusing them back into the body. While this method has led to remarkable success, some cancers develop evasive strategies—mutating or altering their surface proteins to escape detection.

Using human T cells and leukemia cells in specialized mouse models, researchers developed ALA-CART cells to combat this challenge. The modified cells demonstrated an ability to target and destroy acute lymphocytic leukemia (ALL) cells that had previously resisted conventional CAR-T treatments.

“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, corresponding author and member of the University of Colorado Cancer Center. “It also shows signs it could reduce side effects that often accompany traditional therapies.”

A Game-Changer in Cancer Immunotherapy?

Kohler notes that while CAR-T therapy has been a game-changer, its fundamental design has remained largely unchanged for 15 years.

“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,” said Kohler. “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. What was surprising is that we didn’t just fix the problem of leukemia cells escaping—we improved multiple aspects of the ALA-CART cells, and we’re hopeful this will translate into improved outcomes for patients in the future.”

What’s Next?

The next step is moving ALA-CART into clinical trials, where researchers will assess its safety and efficacy in human patients. Danis and her team hope to launch these trials within the next two years.

Beyond leukemia, the researchers are also testing ALA-CART against other cancers, including 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 delivers on its promise, it could redefine how CAR-T therapy is used—giving more patients a fighting chance against cancers that once seemed insurmountable.