CD19 targeting CAR T-cells demonstrate remarkable efficacy in treating B-lineage ALL (BL-ALL). Unfortunately, up to 40% of treated patients relapse with CD19 negative disease. We observed that CD19 loss is associated with preservation of highly variable, yet targetable, expression of CD20 and/or CD22. Accordingly, we reasoned that broadening the spectrum of CD19CAR T-cells to include both CD20 and CD22 will enable them to target CD19(−) escape BL-ALL while preserving their upfront efficacy. We co-expressed individual CAR molecules on T-cells using one tricistronic transgene. TriCAR T-cells effectively killed CD19 negative leukemia cells from patients who relapsed after CD19 directed T-cell therapy, while CD19CAR T-cells were ineffective. At the subcellular level, TriCAR T-cells formed dense immune synapses with target cells, were highly-effective serial killers, and were as efficacious as CD19CAR T-cells against primary CD19 positive disease. Careful evaluation in a well-designed clinical trial would determine whether TriCAR T-cells are best suited for salvage or up-front CAR therapy.