The successful and promising clinical results of adoptive T cell therapies for cancer dictate for further advancements, which would broaden their applicability for more patients and for more diseases. Current approaches require the isolation expansion and reinfusion of tumor infiltrating lymphocytes (TILs), the labor-intensive ex-vivo generation and expansion of tumor antigen-specific T cell lines or the genetic engineering of autologous T cells with tumor antigen specific TCRs, and most recently with Chimeric Antigen Receptors (CARs). Yet, there are still limitations, which impede the progress and broader use of T cell therapies. In many cases the autologous T cell isolation and expansion could be problematic or impossible (e.g immunosuppressed patients after chemotherapy, immune-deficient patients presenting with malignancies). Also, the isolation and ex vivo manipulation of autologous cells requires processing time, which can be critical for the patient’s health. In addition, the existing ex vivo T-cell expansion protocols push T cells to a terminal differentiated effector state at the cost of their regenerative capacity and resulting in exhausted, less persistent cellular products. The development of broadly applicable cellular therapeutics, which have been manufactured, functionally validated and banked in advance, and can be applied beyond HLA histocompatibility limitations would improve the consistency and availability and reduce the cost of adoptive T cell therapy. Towards this future goal, this project explored the feasibility of a novel strategy for generating unlimited, “off the shelf”, safe, antigen-specific T lymphocytes with optimized features across histocompatibility barriers.We specifically focus on developing a universally applicable adoptive therapy for Multiple Myeloma (MM). This malignant disease of antibody producing plasma cells is the 2nd most common hematological malignancy, and accounts for 1.4 % of all cancers and for 1.8 % of all cancer mortality worldwide. Despite four decades of drug innovation MM remains incurable by means of chemotherapy and/or autologous stem cell transplantation.
