T cells modified to express chimeric antigen receptor (CAR) targeting CD19 (CD19CAR) have produced remarkable clinical responses in patients with relapsed/refractory B-cell acute lymphoblastic leukemia. CD19CAR T-cell therapy has also demonstrated prominent effects in B-cell non-Hodgkin lymphoma (B-NHL) patients. However， a subset of patients who relapse after CD19CAR T-cell therapy have outgrowth of CD19 tumor cells. Hence， development of alternative CARs targeting other B-cell markers represents an unmet medical need for B-cell acute lymphoblastic leukemia and B-NHL. Here， we confirmed previous data by showing that， overall， B-NHL has high expression of CD37. A second-generation CD37CAR was designed... More
T cells modified to express chimeric antigen receptor (CAR) targeting CD19 (CD19CAR) have produced remarkable clinical responses in patients with relapsed/refractory B-cell acute lymphoblastic leukemia. CD19CAR T-cell therapy has also demonstrated prominent effects in B-cell non-Hodgkin lymphoma (B-NHL) patients. However， a subset of patients who relapse after CD19CAR T-cell therapy have outgrowth of CD19 tumor cells. Hence， development of alternative CARs targeting other B-cell markers represents an unmet medical need for B-cell acute lymphoblastic leukemia and B-NHL. Here， we confirmed previous data by showing that， overall， B-NHL has high expression of CD37. A second-generation CD37CAR was designed， and its efficacy in T cells was compared with that of CD19CAR. In vitro assessment of cytotoxicity and T-cell function upon coculture of the CAR T cells with different target B-cell lymphoma cell lines demonstrated comparable efficacy between the 2 CARs. In an aggressive B-cell lymphoma xenograft model， CD37CAR T cells were as potent as CD19CAR T cells in controlling tumor growth. In a second xenograft model， using U2932 lymphoma cells containing a CD19 subpopulation， CD37CAR T cells efficiently controlled tumor growth and prolonged survival， whereas CD19CAR T cells had limited effect. We further show that， unlike CD19CAR， CD37CAR was not sensitive to antigen masking. Finally， CD37CAR reactivity was restricted to B-lineage cells. Collectively， our results demonstrated that CD37CAR T cells also can effectively eradicate B-cell lymphoma tumors when CD19 antigen expression is lost and support further clinical testing for patients with relapsed/refractory B-NHL.
