ALA-CART: zeroing in on cancer cells that evade detection
CAR-T cells have been redesigned to improve their ability to target cancer cells that would previously fly under their radar.
Scientists at the University of Colorado Anschutz Medical Campus (CO, USA) have created ALA-CART, an advanced CAR-T therapy aimed at improving therapeutic persistence and effectiveness, especially against cancer cells that evade traditional CAR-T treatments.
CAR T-cells are not sensitive enough to detect and eliminate antigen-low tumor cells — cancer cells that express lower levels of target antigens. This problem has been observed in multiple cancers, including B-cell acute lymphoblastic leukemia, lymphoma and multiple myeloma. The inability to target antigen-low cells not only reduces CAR T-cell efficacy but also limits the range of cancers that can be treated with this therapy.
To address this issue, the researchers focused on understanding antigen sensitivity mechanisms in traditional CAR T-cell therapy by studying a clinically active CD22-targeting CAR (CD22BBz CAR). They analyzed the signaling pathways that are activated when CAR T-cells encounter antigen-low tumor cells and found that antigen-low stimulation led to inefficient LAT (linker for activation of T cells) activation.
Based on these findings, the team designed a bicistronic CAR platform called ALA-CART. This system co-expresses a second-generation CAR alongside an adjunctive LAT-activating CAR, which incorporates the intracellular domain of LAT. This modification enhances LAT activation and strengthens downstream signaling, enabling ALA-CART cells to more effectively target and eliminate cancer cells, even those with low antigen expression.
When tested in leukemia patient-derived xenografts with extremely low CD22 antigen levels (~300 molecules per cell), ALA-CART demonstrated superior efficacy and persistence compared to traditional CAR T-cells. Since ALA-CART can target antigen-low tumor cells that evade traditional CAR-T therapy, it is likely to have a lower risk of relapse.
Additionally, ALA-CART increased the proportion of T stem cell memory cells, which are associated with long-term survival and resistance to exhaustion. This enhancement could lead to more durable responses, ultimately improving treatment outcomes and reducing the likelihood of therapy failure.
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By overcoming the challenge of targeting antigen-low cells and improving durability, the ALA-CART platform shows great promise for enhancing long-term outcomes. The next step for the researchers is to advance ALA-CART into clinical trials to evaluate its safety and efficacy in human patients, with plans to begin within the next two years. In the meantime, they are also testing the therapy on other cancer types, including acute myeloid leukemia, multiple myeloma and solid tumors.