Preclinical development of CD37CAR T-cell therapy for treatment of B-cell lymphoma
Hakan Köksal, Pierre Dillard, Sarah E Josefsson, Solrun Melkorka Maggadottir, Sylvie Pollmann, Anne Fåne, Yngvild Nuvin Blaker, Klaus Beiske, Kanutte Huse, Arne Kolstad, Harald Holte, Gunnar Kvalheim, Erlend B Smeland, June H Myklebust, Else Marit Inderberg, Sébastien Wälchli, Hakan Köksal, Pierre Dillard, Sarah E Josefsson, Solrun Melkorka Maggadottir, Sylvie Pollmann, Anne Fåne, Yngvild Nuvin Blaker, Klaus Beiske, Kanutte Huse, Arne Kolstad, Harald Holte, Gunnar Kvalheim, Erlend B Smeland, June H Myklebust, Else Marit Inderberg, Sébastien Wälchli
Abstract
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.
Conflict of interest statement
Conflict-of-interest disclosure: E.B.S. owns stock in Nordic Nanovector. H.H., G.K., E.B.S., J.H.M., E.M.I., and S.W. have applied for a patent related to the results. The remaining authors declare no competing financial interests.
© 2019 by The American Society of Hematology.
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Source: PubMed