A novel CAR-T cell product targeting CD74 is an effective therapeutic approach in preclinical mantle cell lymphoma models

Wing Keung Chan; Jessica Williams; Kinnari Sorathia; Betsy Pray; Kaled Abusaleh; Zehua Bian; Archisha Sharma; Ian Hout; Shamama Nishat; Walter Hanel; Shelby L Sloan; Aneeq Yasin; Nathan Denlinger; Xiaoli Zhang; Natarajan Muthusamy; Sumithira Vasu; Marcos de Lima; Yiping Yang; Robert Baiocchi; Lapo Alinari

doi:10.1186/s40164-023-00437-8

A novel CAR-T cell product targeting CD74 is an effective therapeutic approach in preclinical mantle cell lymphoma models

Exp Hematol Oncol. 2023 Sep 22;12(1):79. doi: 10.1186/s40164-023-00437-8.

Authors

Wing Keung Chan¹, Jessica Williams¹, Kinnari Sorathia¹, Betsy Pray¹, Kaled Abusaleh¹, Zehua Bian¹, Archisha Sharma¹, Ian Hout¹, Shamama Nishat¹, Walter Hanel¹, Shelby L Sloan¹, Aneeq Yasin¹, Nathan Denlinger¹, Xiaoli Zhang², Natarajan Muthusamy¹, Sumithira Vasu¹, Marcos de Lima¹, Yiping Yang¹, Robert Baiocchi¹, Lapo Alinari³

Affiliations

¹ Department of Internal Medicine, Division of Hematology, College of Medicine, The Ohio State University, 400 W. 12th Ave, 481D Wiseman Hall, Columbus, OH, 43210, USA.
² Department of Biomedical Informatics/Center for Biostatistics, The Ohio State University, Columbus, OH, 43210, USA.
³ Department of Internal Medicine, Division of Hematology, College of Medicine, The Ohio State University, 400 W. 12th Ave, 481D Wiseman Hall, Columbus, OH, 43210, USA. lapo.alinari@osumc.edu.

Abstract

Background: Mantle cell lymphoma (MCL) is a rare B-cell non-Hodgkin lymphoma subtype which remains incurable despite multimodal approach including chemoimmunotherapy followed by stem cell transplant, targeted approaches such as the BTK inhibitor ibrutinib, and CD19 chimeric antigen receptor (CAR) T cells. CD74 is a nonpolymorphic type II integral membrane glycoprotein identified as an MHC class II chaperone and a receptor for macrophage migration inhibitory factor. Our group previously reported on CD74's abundant expression in MCL and its ability to increase via pharmacological inhibition of autophagosomal degradation. Milatuzumab, a fully humanized anti-CD74 monoclonal antibody, demonstrated significant activity in preclinical lymphoma models but failed to provide meaningful benefits in clinical trials mainly due to its short half-life. We hypothesized that targeting CD74 using a CAR-T cell would provide potent and durable anti-MCL activity.

Methods: We engineered a second generation anti-CD74 CAR with 4-1BB and CD3ζ signaling domains (74bbz). Through in silico and rational mutagenesis on the scFV domain, the 74bbz CAR was functionally optimized for superior antigen binding affinity, proliferative signaling, and cytotoxic activity against MCL cells in vitro and in vivo.

Results: Functionally optimized 74bbz CAR-T cells (clone 42105) induced significant killing of MCL cell lines, and primary MCL patient samples including one relapse after commercial CD19 CAR-T cell therapy with direct correlation between antigen density and cytotoxicity. It significantly prolonged the survival of an animal model established in NOD-SCIDγc^-/- (NSG) mice engrafted with a human MCL cell line Mino subcutaneously compared to controls. Finally, while CD74 is also expressed on normal immune cell subsets, treatment with 74bbz CAR-T cells resulted in minimal cytotoxicity against these cells both in vitro and in vivo.

Conclusions: Targeting CD74 with 74bbz CAR-T cells represents a new cell therapy to provide a potent and durable and anti-MCL activity.

Keywords: CD74; Chimeric antigen receptor; Mantle cell lymphoma.

Abstract

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