Dominant negative PD1 armored CART cells to induce remission in relapsed or refractory non-Hodgkin lymphoma (NHL) patients.

e15028 Background: The chimeric antigen receptor (CAR) T cell treatment has been demonstrated as an effective therapy to treat relapsed/refractory B cell malignancy. However, tumor microenvironment influences and affects the efficacy of CAR T treatment. For example, programmed death ligand 1/2 (PDL1/2) may inhibit the CAR T cells via interaction with up-regulated programmed cell death protein 1 (PD1) after T cells activation, suppressing the tumor-killing capability of the CAR T cells. Thus, blockade of the PD1-PDL1/2 interaction may enhance the anti-tumor efficacy of CAR T therapy. Methods: Here, we generated CAR T expressed an anti-CD19 CAR molecule and a dominant-negative PD1 molecule. Compared with conventional CART cells, these “armored” CART cells showed the enhanced capability of tumor-killing and more “memory-like” phenotypes after multiple-round tumor challenging. These results suggest dominant-negative PD1 molecules may protect CART cells from exhaustion in the tumor microenvironment. Results: Further, we reported the findings of a clinical trial for six relapsed or refractory B-cell non-Hodgkin lymphoma (NHLs) patients treated using our armored CAR T cells. These six patients failed multiple rounds of chemotherapy and radiotherapy. In the clinical trial, the patients were infused with autologous CAR T cells range from1×106/kg to 8×106/kg. PET/CT showed significant tumor shrinkage and SUV max declines in all six patients, and the ongoing responses were monitored. The best overall response rate (ORR)was 100%. Conclusions: The results of these six patients in the clinical trial showed that our armored CAR T cells achieved the significant anti-bulky lymphoma response while causing limited and tolerated cytokine release syndrome and central nervous system toxicity. Thus, dominant-negative PD1 molecules may increase CAR T cells persistence in patients, enhancing the efficacy of CAR T cells for treating blood cancer. Finally, dominant-negative PD1 can be used as a platform technology and may be applied to other adoptive cellular immunotherapies such as TCR-T or TIL in the treatment of solid tumors. We are continuing to monitor current patients and recruit more patients for the clinical trial.