Abstract CT191: First-in-human, dose escalation and expansion study of MT-6402, a novel engineered toxin body (ETB) targeting PD-L1, in patients with PD-L1 expressing relapsed/refractory advanced solid tumors: Interim data
Authors: Van Tine Brian A. , Ahn Eugene , Redman Rebecca A. , Barve Minal A. , Edenfield William J. , Peguero Julio , Villaflor Victoria M. , Rasco Drew W. , Powell Steven F. , Mamuye Admasu T. , Moore Chris B. , Pelham Joshua M. , Charoenthongtrakul Soratree , Spigel David R. 
Published: April 2024

Abstract
MT-6402 is a PD-L1-targeted ETB capable of directly killing PD-L1 expressing cells by internalization of a de-immunized Shiga-like toxin A subunit (SLTA), resulting in ribosomal destruction. Targeting PD-L1 expressing tumor cells may directly drive tumor regression, whereas targeting PD-L1 expressing immune cells may release immunosuppression and drive tumor immune recognition. MT-6402 also delivers an HLA-A*02 restricted cytomegalovirus (CMV) class I antigen into PD-L1 expressing cells (antigen seeding) that can be recognized by existing CMV-specific cytotoxic T cells. A first-in-human dose escalation (Part A) and expansion (Part B) study with a weekly intravenous administration of MT-6402 in 4-week cycles was initiated in 2021. Safety and tolerability are primary objectives. Efficacy, pharmacokinetics, and pharmacodynamic data are also collected. As of 10Dec2023, 53 total patients (pts) with PD-L1-expressing advanced solid tumors received ≥ 1 dose of MT-6402: 48 pts in Part A ranging in dose 16 to 100 µg/kg and 5 pts in Part B at 63 µg/kg, just below the maximum tolerated dose (MTD) of 83 µg/kg. MT-6402 was well tolerated in Part A, completed Sept2023. 5 dose limiting toxicities have been reported: a Grade (G)3 maculopapular rash at 24 µg/kg, a G3 infusion related reaction at 63 µg/kg, a G1 cardiac troponin T increase leading to dosing hold for ≥2 weeks at 83 µg/kg, a G3 maculopapular rash at 100 µg/kg, and a G1 cardiac troponin T increase at 100 µg/kg. There were no G4 or G5 drug-related adverse events. In Part B, pts with PD-L1 scores of TPS ≥ 50% will be treated at MTD or lower and 5 pts have been treated at 63 µg/kg. Signs of antitumor activity have been reported including a long-lasting PR with 70% tumor reduction have been observed in a pt with CPI-refractory nasopharyngeal carcinoma on treatment 14+ cycles at 63 µg/kg. This pt has a PD-L1 TPS score of 2% indicating immune cell clearance may have driven the response. The most common cancer in Part A is Squamous Cell Carcinoma of the Head and Neck (10 pts). Pharmacodynamic effects include a significant reduction in peripheral PD-L1+ immune cells, indicating a PD-L1 target-specific effect. Substantial alterations in serum cytokines associated with the tumor microenvironment were noted after each dose in most pts in a dose dependent manner. Most pts display increased CD8/CD4 ratios with IL-2 and TNFα cytokine release, indicative of immune activation due to elimination of immune cells. CMV-specific CD8 T-cells exhibited a pattern of extravasation from the periphery in HLA-A*02+/CMV+ pts suggesting antigen seeding. These results describe a novel approach to checkpoint modulation by MT-6402 with targeted cell killing and altered tumor immunophenotype, particularly in HLA-A*02/CMV+ pts. These results provide rationale for continued development of MT-6402.
Citation Format: Brian A. Van Tine, Eugene Ahn, Rebecca A. Redman, Minal A. Barve, William J. Edenfield, Julio Peguero, Victoria M. Villaflor, Drew W. Rasco, Steven F. Powell, Admasu T. Mamuye, Chris B. Moore, Joshua M. Pelham, Soratree Charoenthongtrakul, David R. Spigel. First-in-human, dose escalation and expansion study of MT-6402, a novel engineered toxin body (ETB) targeting PD-L1, in patients with PD-L1 expressing relapsed/refractory advanced solid tumors: Interim data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT191.