CD79b and CD19 are associated with B cell signaling and expressed on most B cell lymphomas. Ormhøj et al. show that CD79b expression persisted on a mantle cell lymphoma (MCL) line despite CD19 knockout in vitro. Chimeric antigen receptor (CAR) T cells specific for CD79b or CD19, or for CD79b plus CD19 were generated. All the CAR T cells lysed MCL cell lines in vitro and cleared CD79b+CD19+ MCLs in murine xenograft models. CD79b-specific CAR T cells and the bispecific CAR T cells also cleared CD79b+CD19- MCLs. Targeting CD79b with or without CD19 may provide benefit upfront or for CD19- lymphoma recurrence.
Contributed by Paula Hochman
PURPOSE: T cells engineered to express a chimeric antigen receptor (CAR) against CD19 have recently been FDA-approved for the treatment of relapsed or refractory large B cell lymphoma. Despite the success and curative potential of CD19 CAR T cells, several reports describing disease relapse due to antigen loss are now emerging. EXPERIMENTAL DESIGN: We developed a novel CAR construct directed against CD79b, a critical receptor for successful B cell development that remains highly expressed in several subtypes of B cell lymphoma, including mantle cell lymphoma (MCL). We tested CAR T cells directed against CD79b alone or in combination with CD19 targeting in a single construct, against cell line- and patient-derived xenograft models. RESULTS: We demonstrate CAR79b antigen-specific recognition and cytotoxicity against a panel of cell lines and patient-derived xenograft models of MCL. Importantly, we show that downregulation of CD19 does not influence surface expression of CD79b and that anti-CD79b CAR T cells alone or arranged in a dual-targeting format with a CD19 single-chain variable fragment (scFv) are able to recognize and eliminate CD19-positive, CD19-negative, and mixed CD19+/CD19- B cell lymphoma. CONCLUSIONS: Our findings demonstrate that CAR T cells targeting CD79b alone or in combination have promise for treating and preventing CD19 antigen escape in B cell lymphomas.