Patients with chemotherapy-refractory, diffuse large B-cell lymphoma (DLBCL) have poor prognoses. CD19 and CD20 are promising targets for the treatment of B-Cell malignancies. However, despite the initial promising results from anti-CD19 CAR therapy, only 30-35% of patients with DLBCL achieve remissions lasting longer than 2-3 years after anti-CD19 CAR T-cell therapy. Relapse and non-response are likely due to diminished CD19 expression after anti-CD19 therapy and low expression of CD19 in some lymphomas.
To overcome the limitations of the CD19 CAR T therapy, inventors developed an improved CAR targeting both CD19 and CD20. CARs targeting both CD19 and CD20 showed greater efficacy than the CD19 targeting CAR by itself. The structure of the CD20 binder in some of these CAR constructs is optimized to reduce death of CAR-expressing T cells and to promote retention of CAR expression. Also, these constructs are optimized to reduce retroviral recombination events.