CD19 occupancy with tafasitamab increases therapeutic index of CART19 cell therapy and diminishes severity of CRS

• CD19 occupancy with CD19 monoclonal antibody leads to less activation of CART19, which reduces CAR T apoptosis and tumor cell pyroptosis.

• Sequential therapy of tafasitamab followed by CART19 results in enhanced antitumor activity of CART19 and lower CRS severity after CART19.

In the development of various strategies of anti-CD19 immunotherapy for treatment of B-cell malignancies, it remains unclear whether CD19 monoclonal antibody therapy impairs subsequent CD19-targeted chimeric antigen receptor T-cell (CART19) therapy. We evaluated the potential interference between the CD19-targeting monoclonal antibody tafasitamab and CART19 treatment in preclinical models. Concomitant treatment of tafasitamab and CART19 showed major CD19 binding competition, which led to CART19 functional impairment. However, when CD19⁺ cell lines were pretreated with tafasitamab overnight and the unbound antibody was subsequently removed from the culture, CART19 function was not affected. In preclinical in vivo models, tafasitamab pretreatment demonstrated reduced incidence and severity of cytokine release syndrome and exhibited superior anti-tumor effect and overall survival compared to CART19 alone. This was associated with transient CD19 occupancy with tafasitamab, which in turn resulted in inhibition of CART19 overactivation, which led to diminished CAR T apoptosis and pyroptosis of tumor cells.