ALA-CART: A Breakthrough CAR-T Cell Therapy Against Resistant Leukemia

Research study background

Researchers at our Center for Cancer and Blood Disorders at Children’s Hospital Colorado have developed a novel strategy that effectively addresses critical weaknesses in current chimeric antigen receptor (CAR) T cell therapies, demonstrating significant potential to enhance long-term outcomes across a broad range of cancers. 

Many patients with relapsed or treatment-resistant B-cell acute lymphoblastic leukemia (B-ALL), the most common childhood cancer, will achieve temporary remission after undergoing second-generation CAR-T cell immunotherapy. However, the disease often returns, especially in therapies that specifically target CD22 antigens. Reporting their findings in a recent issue of Cancer Cell, our investigators demonstrated that leukemia cells with reduced CD22 expression do not evade detection by CAR-T cells, but rather blunt the CAR-T cell response. This low antigen stimulation results in insufficient activation of the linker for activation of T cells (LAT) in second-generation CAR-T cells, which limits the downstream signaling necessary for T cell activity, allowing for leukemia escape and relapses.

“Based on this, we developed the adjunctive LAT-activating CAR-T cell (ALA-CART) platform that can better target leukemias that would otherwise escape from current treatments,” says M. Eric Kohler, MD, PhD, pediatric hematologist oncologist and the corresponding study author.

ALA-CART incorporates an additional component that boosts signaling pathways in the CAR-T cells, enabling them to respond more effectively even when faced with diminished CD22 antigen levels.

To test their novel platform, researchers conducted in vitro experiments and found that the ALA-CART cells proliferated more and killed leukemia better than second-generation CAR-T cells due to their enhanced signaling though LAT. Additionally, global transcriptomic analysis suggested the ALA-CART cells were “younger” and more fit than their second-generation counterparts. This bore out in xenograft mouse models, where the researchers found the ALA-CART cells to have enhanced longevity.

The team assessed the effectiveness of ALA-CART cells against antigen low leukemia cells in vivo by engrafting immunocompromised mice with human leukemia that expressed low levels of the antigen CD22. While standard second-generation CAR-T cells mildly slowed the progression of the leukemia, the ALA-CART cells were able to completely eradicate the leukemia in all treated mice. The team found the increased effectiveness of the ALA-CART cells was not associated with increased inflammatory cytokines, which drive the most common toxicities of current CAR-T cell therapies.

“Our ALA-CART platform has the potential to transform the treatment of children with relapsed B-ALL by overcoming many obstacles that limit the long-term benefit of current CAR-T cell therapy,” Dr. Kohler says.

Clinical implications

The team is currently investigating how various cancers respond to ALA-CART treatment. In addition to studying acute myeloid leukemia — which has shown lower efficacy compared to CAR-T cells targeting B-ALL — they are also examining pediatric solid tumors, including Ewing’s sarcoma and osteosarcomas. The study authors noted that they are developing clinical trials to translate their laboratory findings into ALA-CART cell treatments for patients.