A PHASE I/IIa TRIAL USING CD19-TARGETED THIRD GENERATION CAR T CELLS FOR LYMPHOMA AND LEUKEMIA

Purpose: CAR T cell therapy has been effective for patients with CD19+ B cell malignancies. Most studies have investigated second generation CARs with either CD28 or 4-1BB co-stimulatory domains in the CAR receptor. Here we describe the first clinical phase I/IIa trial using third generation CAR T cells targeting CD19 to evaluate safety and efficacy. Experimental Design: Fifteen patients with B cell lymphoma or leukemia were treated with CAR T cells. The lymphoma patients received chemotherapy during CAR manufacture and eleven of fifteen were given low dose cyclophosphamide and fludarabine conditioning prior to CAR infusion. Peripheral blood was sampled before and at multiple time points post CAR infusion to evaluate the persistence of CAR T cells and for immune profiling, using quantitative PCR, flow cytometry and a proteomic array. Results: Treatment with third generation CAR T cells was generally safe with four patients requiring hospitalization due to adverse reactions. Six of the fifteen patients had initial complete responses (4/11 lymphoma and 2/4 ALL), and three of the lymphoma patients were in remission at 3 months. Two patients are still alive. Best predictor of response was a good immune status prior to CAR infusion with high IL12, DC-Lamp, Fas ligand and TRAIL. Responding patients had low monocytic MDSCs (CD14+CD33+HLA-DR-) and low levels of IL6, IL8, NAP3, sPDL1 and sPDL2. Conclusions: Third generation CARs may be efficient in patients with advanced B-cell lymphoproliferative malignancy with only modest toxicity. Immune profiling pre and post treatment can be used to find response biomarkers.

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