Dual CAR T-Cells to Treat Multiple Myeloma

Multiple Myeloma (MM) is a clonal malignancy of plasma cells. Patients with standard-risk myeloma have a median overall survival of 6–7 years, while those with high-risk disease have a median survival of less than 2–3 years. Despite recent progress in drug development, MM remains incurable mostly due to the development of recurrent disease that resists available therapeutic agent(s). Here, we show the construction of chimeric, antibody-based receptors (CAR) to redirect T cells for adoptive cell treatment of MM. CAR T cell therapy, pioneered in our lab, is a powerful tool for cancer treatment. This approach has proven very effective in clinical trials in leukemia and lymphoma patients and has recently gained FDA approval to treat certain types of large B-cell lymphomas.

Today, the major challenge in the CAR T cell field is to prevent `off-tumor on-target` toxicity, namely, the risk of damage to the patient`s healthy tissues which also express the target antigen of the selected CAR. We took advantage of the surface expression of several antigens that are widely expressed on MM cells and are poorly expressed by hematopoietic stem cells, generating CAR T cells with dual specificity expressing two complementary CARs (dual CARs) for the specific and effective treatment of MM. The complementary chimeric receptors transmit a full T cell activation signal only upon dual engagement with tumor-associated antigens. Here we show the killing effect in vitro, and the superior survival curve of mice treated with dual CAR T cells without unwanted effects against healthy tissue.