Background: MT-6402 is a unique and potent PD-L1-targeted engineered toxin body (ETB) capable of directly killing PD-L1 expressing tumor and immune cells by internalization of a fused Shiga-like toxin A subunit (SLTA) resulting in permanent SLTA-mediated ribosomal inactivation. The targeting of PD-L1 expressing tumor cells may directly drive tumor regression whereas targeting of PD-L1 expressing immune cells may release immunosuppression and drive immune recognition of the tumor. 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. Methods: A first-in-human dose escalation and expansion study in patients with PD-L1-expressing advanced solid tumors was initiated in 2021. As of 1 Jan 2022, 6 patients received at least one dose of MT-6402, 4 of whom were eligible for Dose Limiting Toxicity (DLT) assessment in Cohort 1. Results: A significant reduction in CD14+ monocytes starting in cycle 2 was observed in patients on therapy after each MT-6402 administration, indicating an HLA-independent PD effect consistent with preclinical observations. 5 of 6 patients had a marked decrease in Monocytic Myeloid Derived Suppressor Cells (MDSC). The reduction in MDSC and monocytes in the periphery overlapped with increased CCL2 levels, a chemokine that directs movement of myeloid cells. One patient with osseous metastases from non-small cell lung cancer (NSCLC) who is HLA-A*02 and CMV+ showed complete CMV-specific T-cell extravasation at day 8 and serum cytokine signatures consistent with antigen dependent responses and T cell mobilization. This patient had reduced tracer uptake of metastatic bone lesions with 3/4 lesions resolving completely. A second HLA A*02 CMV+ patient followed a similar trend towards loss of peripheral CMV-specific T cells with a concurrent increase in total CD8 T cells. The CD8 T cells from these 2 patients had elevated T-bet expression from baseline, indicating antigen specific TCR stimulation and expansion. The activated immune response was also accompanied by increased IP-10 and IL-2 cytokine signatures in the serum. Consistent with these findings, one of these two patients had transient (1-12 h) grade 2 infusion related reaction and the other had transient (1-12 h) grade 2 cytokine release syndrome, both on Day 15. These results describe a novel approach to checkpoint modulation by MT-6402, that adds antigen seeding to PD-L1 directing mechanisms. MT-6402 was well tolerated and no DLT was observed in Cohort 1 (16 µg /kg, QW in 4-week cycles). Conclusions: Dose escalation is ongoing. The results hold promise for development of MT-6402 for solid tumors, including in the R/R setting. Data for additional patients will be presented at the meeting. Clinical trial information: NCT04795713.