PD-1 blockade modulates chimeric antigen receptor (CAR)–modified T cells: refueling the CAR

Antibodies blocking the programmed death 1 receptor (PD-1) on T cells produce tumor regression in multiple cancers by disrupting the PD-L1/ PD-1 (programmed death-ligand 1/programmed cell death protein 1) immune inhibitory axis.[1][2][3][4][5] This approach to cancer immunotherapy would seem to be an ideal partner for chimeric antigen receptor (CAR)modified T-cell therapies but is, as yet, untested in this setting.We report a case in which a PD-1 blocking antibody was administered to a patient with refractory diffuse large B-cell lymphoma (DLBCL) and progressive lymphoma after therapy with CAR-modified T cells directed against CD19 (CART19).Following PD-1 blockade, the patient had a clinically significant antitumor response, an expansion of CART19 cells, and decreased coexpression of PD-1 and Eomes by CART19 cells.This case suggests that PD-1 blockade can be effective against cancers failing to respond to CAR-modified T-cell therapy.It also suggests that the PD-1 pathway may be critical in determining the response to CAR-modified T-cell immunotherapy.A 35-year-old man with multiply pretreated, refractory DLBCL of primary mediastinal origin with extranodal involvement of small intestine at diagnosis, and mediastinum, lung, myocardium, and pericardium at progression was treated on a clinical trial at the University of Pennsylvania with autologous CART19 cells expressing murine anti-CD19 scFv and 4-1BB-CD3z costimulatory-activation domains (NCT02030834). 6 CART19 cells were manufactured as previously reported.7,8 He received lymphodepleting chemotherapy with hyperfractionated cyclophosphamide (300 mg/m 2 3 6 doses), followed by autologous CART19 cell infusion (5 3 10 8 CART19 cells or 5.34 3 10 6 cells/kg), day 0. Follow-up chest computed tomographic (CT) scan performed on day 26 to evaluate worsening dyspnea showed Day 45 Day 26