Anti-CD19 Monoclonal antibody, clone IJC20 [APC]

Natural killer (NK) cells have a potent cytotoxic activity against leukemia and lymphoma without recognition of human leukocyte antigen (HLA) molecules. Chimeric antigen receptor-engineered NK cells (CAR-NK cells) can be produced from the NK92 cell line, peripheral blood, cord blood, and induced pluripotent stem cells for immunotherapy of malignant tumor cells. Recently, the safety and efficacy of HLA-mismatched allogeneic cord blood-derived CD19 CAR-NK cell therapy for CD19-positive hematological malignancies have been reported. However, the durability of clinical effects has not been clarified. The characteristics of CAR-NK cells with a strong antileukemia/lymphoma effect and better proliferative capacity without severe adverse effects may be promising for overcoming intractable hematological malignancies as an off-the-shelf allogeneic cellular therapy.

Simple Summary In relapsed, refractory B cell malignancies and multiple myeloma, chimeric antigen receptor (CAR) T cell therapy has represented a major scientific advancement with high response rates and durable responses for many. Nonetheless, target antigen downregulation in tumor cells can lead to poor responses and relapsed disease. Current FDA approved CAR T cell therapies only target a single B-cell specific cell marker. While effective, single targeted CAR T cell therapy can lead selective pressure against the target antigen leading to loss of expression and tumor cell escape. Simultaneous dual antigen targeting CAR therapy has been evaluated in multiple early phase clinical trials in response to these clinical challenges in hopes of improving response rates and preventing relapse. This article discusses the limitations of single targeted CAR T cell therapy, approaches to dual antigen targeting, and the results of early phase trials utilizing dual antigen targeting CAR T cell therapy. Chimeric antigen receptor (CAR) modified T cell therapy offers a targeted immunotherapeutic approach to patients with refractory hematological malignancies. This technology is most advanced in B cell malignancies and multiple myeloma and is rapidly evolving as more data become available regarding clinical efficacy and response durability. Despite excellent initial response rates with single antigen targeting CARs, failure to respond to therapy and relapse due to target antigen downregulation remain clinical challenges. To mitigate immunophenotypic selective pressures, simultaneous dual antigen targeting with bispecific CAR T cells or multiple administration of different populations of CAR T cells may prevent relapse by addressing one resistance mechanism attributed to antigenic loss. This article will review recently published data on the use of dual targeting with CAR T cells from early phase clinical trials aimed at treating B cell malignancies and multiple myeloma.