Overcoming CD19-Negative Relapses in Patients with B-Cell Lymphomas Treated with Tisagenlecleucel

Abstract

Anti-CD19 chimeric antigen receptor T cell (CART) immunotherapy has revolutionized the treatment of large B-cell lymphomas (LBCL). However, up to 70% of LBCL patients (pts) ultimately fail CART treatment. Several mechanisms of relapse have been described, such as T cell exhaustion, an immunosuppressive tumor microenvironment, and antigen-negative escape. While antigen-negative relapse after anti-CD19 CART (CART19) is well studied in acute B lymphoblastic leukemia, less data are available for LBCL, especially in pts treated with the 4-1BB costimulated CART19, tisagenlecleucel (tisa-cel, formerly CTL019). In this study, we evaluated the frequency of CD19 loss in LBCL pts treated with tisa-cel and identified CD79 as an antigen highly expressed by immunohistochemistry (IHC) in CD19-negative biopsies. We then generated and optimized an anti-CD79 CART (CART79) and subsequently cloned a dual anti-CD79b/anti-CD19 CART that showed high potency against CD19-neg models.