Chimeric antigen receptor (CAR) T-cell therapy has emerged as a revolutionary treatment for various cancers. This innovative approach involves modifying a patient’s T cells to express CARs, engineered receptors that enable the T cells to recognize and eliminate cancer cells. While highly effective, CAR T-cell therapy can lead to severe side effects due to “on-target off-tumor” toxicity, where healthy cells expressing the target antigen are also attacked. This has spurred research into refining CAR T-cell therapy to enhance its safety and efficacy.
One promising target for CAR T-cell therapy in multiple myeloma (MM) is CD229, a protein found on the surface of MM cells. However, healthy lymphocytes also express CD229, albeit at lower levels, posing a risk of unintended damage. To mitigate this risk, researchers have explored strategies to increase the selectivity of CD229 CAR T cells for MM cells.
A key approach to enhancing CAR T-cell selectivity involves modifying the CAR’s binding domain to reduce its affinity for the target antigen. By fine-tuning the interaction between the CAR and CD229, researchers aim to create CAR T cells that effectively target MM cells while sparing healthy lymphocytes. This involves meticulous screening of variant binding domains using techniques like solid-phase binding assays and biolayer interferometry.
These assays allow researchers to quantify the binding strength of different CAR variants to CD229, enabling the identification of CARs with optimal affinity. Subsequent testing of these variant CAR T cells against MM cells and healthy lymphocytes in vitro and in vivo helps determine their cytotoxic activity and selectivity.
In a significant advancement, researchers identified a CD229 CAR binding domain with micromolar affinity that, when combined with c-Jun overexpression, demonstrated potent anti-tumor activity comparable to conventional CD229 CAR T cells. Crucially, this modified CAR T cell lacked the cytotoxic activity against healthy lymphocytes observed in the parental cells, both in laboratory and animal models.
This breakthrough represents a significant step towards improving the safety and efficacy of CAR T-cell therapy. By reducing the risk of off-target toxicity, this refined approach holds the potential to expand the application of CAR T-cell therapy to a wider range of patients. While further clinical validation is necessary, these findings offer a promising avenue for enhancing cancer treatment with reduced side effects. The research highlights the ongoing efforts to fine-tune CAR T-cell therapies, aiming to maximize their cancer-fighting potential while minimizing harm to healthy tissues.
