Abstract
Simple SummaryChimeric antigen receptor (CAR) T cell therapy represents a major advancement in cancer treatment. Recently, FDA approved CAR-T cells directed against the CD19 protein for treatment of leukemia and lymphoma. In spite of impressive clinical responses with CD19-CAR-T cells, some patients demonstrate disease relapse due to either antigen loss, cancer heterogeneity or other mechanisms. Novel CAR-T cells and targets are important for the field. This report describes novel CD37, humanized CD37 and bispecific humanized CD37-CD19-CAR-T cells targeting both CD37 and CD19. The study demonstrates that these novel CAR-T cells specifically targeted either CD37 positive or CD37 and CD19-positive cells with endogenous and exogenous protein expression and provides a basis for future clinical studies.CD19 and CD37 proteins are highly expressed in B-cell lymphoma and have been successfully targeted with different monotherapies, including chimeric antigen receptor (CAR)-T cell therapy. The goal of this study was to target lymphoma with novel CD37, humanized CD37, and bi-specific humanized CD37-CD19 CAR-T cells. A novel mouse monoclonal anti-human CD37 antibody (clone 2B8D12F2D4) was generated with high binding affinity for CD37 antigen (KD = 1.6 nM). The CD37 antibody specifically recognized cell surface CD37 protein in lymphoma cells and not in multiple myeloma or other types of cancer. The mouse and humanized CD37-CAR-T cells specifically killed Raji and CHO-CD37 cells and secreted IFN-gamma. In addition, we generated bi-specific humanized hCD37-CD19 CAR-T cells that specifically killed Raji cells, CHO-CD37, and Hela-CD19 cells and did not kill control CHO or Hela cells. Moreover, the hCD37-CD19 CAR-T cells secreted IFN-gamma against CD37-positive and CD19-positive target CHO-CD37, Hela-CD19 cells, respectively, but not against CD19 and CD37-negative parental cell line. The bi-specific hCD37-CD19 significantly inhibited Raji xenograft tumor growth and prolonged mouse survival in NOD scid gamma mouse (NSG) mouse model. This study demonstrates that novel humanized CD37 and humanized CD37-CD19 CAR-T cells specifically targeted either CD37 positive or CD37 and CD19-positive cells and provides a basis for future clinical studies.
Highlights
Chimeric antigen receptor (CAR) T cell therapy is an exciting and novel area of immuno-oncology research [1,2,3]
CD37 is highly expressed in many hematological cancers, such as non-Hodgkin’s lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), and in some peripheral and cutaneous T cell lymphomas [20,21,22], and absent or weakly expressed in multiple myeloma and Hodgkin’s lymphoma [23]
Several murine anti-human CD37 mAbs were isolated from hybridoma and screened for binding to recombinant human CD37-Maltose binding protein (MBP)-His antigen (Figure 1A) and seven other unrelated proteins (Figure 1B)
Summary
Chimeric antigen receptor (CAR) T cell therapy is an exciting and novel area of immuno-oncology research [1,2,3]. CAR-T cells have been tested against several targets for hematological cancers, such as CD19, CD20, CD22, CD123, BCMA, and others in clinical trials [4,5,6,7,8,9,10,11,12,13]. Novel approaches and targets are being developed to overcome challenges to existing cell therapies, such as loss of antigen, an immunosuppressive tumor microenvironment, and limited persistence of CAR-T cells [4,12,14,15,16,17]. CD37 plays a role in integrin, AKT, PI3-Kinase-dependent survival, and apoptotic signaling, motility, immune response signaling via activation of dendritic cell migration [25,26]
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