AbstractAdoptive immunotherapy with T cells that were modified by gene-transfer to express a tumor-targeting chimeric antigen receptor (CAR) is being investigated as a novel and transformative way for treating cancer. CARs are synthetic receptors with an extracellular antigen-binding domain derived from the VH/VL chains of an antibody, an intracellular signaling domain and recognize surface molecules independent from HLA. The CAR-transgene in MM mainly targeting BCMA can be inserted into autologous T cells to provide a personalized tumor-reactive T-cell product for an individual patient. Since 2019 BCMA-directed CAR T cell therapy is used for the treatment of relapsed/refractory MM (RRMM) in phase 1 / 2 trials. Phase 3 trials sponsored by different pharmaceutical companies were started for RRMM in 2019.
An ongoing effort in the field is to identify alternative tumor antigens to extend applications of CAR T-cell therapy in Multiple Myeloma. Several novel CAR antigens are currently being validated in pre-clinical and clinical trials.
In one approach, we redirected the specificity of T cells through expression of a chimeric antigen receptor (CAR) directed against SLAMF7 derived from the antibody and demonstrate that CAR T cells prepared from patients and healthy donors confer potent antimyeloma reactivity.
The data illustrate the potential use of CAR T-cell therapy as an effective treatment against multiple myeloma and provide novel insights into the consequences of targeting T cells for the normal lymphocyte compartment. The results have been encouraging in most of these trials with high efficacy even in patients that had received several lines of prior therapy or even including patients with extramedullary disease.