UMG1 Defines a Targetable Subset of T-Cell Lymphomas and Enables Precision Immunotherapy With a First-in-Class CD3ε Bispecific Engager.

T-cell lymphomas (TCLs) account for a relatively small fraction of lymphoid malignancies and are characterized by highly aggressive course often refractory to current available therapies. We previously reported potent in vitro and in vivo antitumor activity of a Bispecific T-Cell Engager (UMG1/CD3ε-BTCE) directed against UMG1, a unique CD43 epitope that is abundantly expressed on T-cell acute lymphoblastic leukemia (T-ALL) and diffuse large B-cell lymphoma (DLBCL) cells, while absent in most normal tissues, except thymocytes and a small fraction of peripheral blood T lymphocytes (< 5%). Here, we investigated the in vitro efficacy of UMG1/CD3ε-BTCE against TCLs. IHC analysis of Tissue Micro Arrays (TMAs) revealed high UMG1 expression in 62.3% of TCL samples, including peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) and ALK-negative anaplastic large cell lymphoma (ALCL). Notably, all T-PLL primary specimens (27/27) were positive, and 3 of 4 TCL cell lines also expressed UMG1 by flow cytometry. The asymmetric UMG1/CD3ε-BTCE induced robust redirected cytotoxicity against UMG1-expressing TCL cells. Moreover, this activity was strengthened by cell exposure to the HDAC inhibitor SAHA. We observed a dose-dependent engaged T-cell-mediated cytotoxicity and inflammatory cytokine release, resulting in lysis of UMG1-expressing cells, with no significant effect on UMG1-not expressing cells. Our findings suggest that the UMG1/CD3ε-BTCE selectively exerts potent anti-tumor activity against a relevant subset of TCLs. These findings support the development of a precision immunotherapy approach for patients with UMG1-expressing aggressive hematologic malignancies.