Based on in vitro and in vivo preclinical data, tri-specific CD19xCD20xCD22 VHH CAR-T can be effective targeting tumors lack of CD19 expression, therefore, it has the potential of treating relapsed patients with prior CD19 CAR-T therapy. The feasibility of making tri-specific CAR-T would help to extend this technology to solid cancers where heterogeneity poses a major challenge at current stage.