Background: MT-6402, an engineered toxin body (ETB) , has been designed to be effective in patients (pts) previously treated with checkpoint inhibitors (CPIs) by utilizing 3 unique mechanisms of action (MOA): (i) remodeling of the tumor microenvironment by elimination of PD-L1⁺ immunosuppressive cells like myeloid-derived suppressor cells (MDSCs), (ii) direct cell kill of PD-L1⁺ expressing tumor cells, (iii) delivery of HLA-A*02 restricted cytomegalovirus (CMV) peptide pp65 to PD-L1 expressing cells to direct a CMV specific CD8 T-cell response against the tumor. Methods: Dose escalation continues with MT-6402 (QW in 4-week cycles) in pts with relapsed/refractory PD-L1⁺ solid tumors. After clearing doses of 16, 24, 32, 42 and 63 µg/kg, 83 µg/kg is being evaluated. Safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamic data are reported. Results: MT-6402 at 63 µg/kg in 1 pt with metastatic nasopharyngeal carcinoma (NPC) who progressed after radiation, chemotherapy, and CPI (PD-L1 CPS=2%, not HLA-A*02) resulted in a PR (63% reduction in target lesion) after 2 cycles. This pt had an increase in CD8/CD4 and immune activation cytokines (IL-2, TNFα, IFNγ) consistent with elimination of MDSCs. A pt with NSCLC (osseous disease only) that had progressed after CPI showed resolution of 3/4 osseous metastases and decreased radiotracer uptake by the remaining bone metastasis. This patient had high PD-L1 tumor expression and HLA-A*02/CMV⁺. Complete CMV-specific T-cell extravasation was noted by C1D8 consistent with haplotype-specific CMV antigen delivery for presentation on the tumor surface by MHC class I. All cohorts had reductions in peripheral PD-L1⁺ MDSCs, monocytes and dendritic cells after MT-6402 without effect on PD-L1^- cells with the most depletion at the highest doses. Most pts displayed CD8⁺ T-cell expansion and elevations of serum IL-2 and TNFα, consistent with PD-L1-mediated immunotolerance. MT-6402 was well tolerated with 2 dose limiting toxicities reported: Grade (G)2 maculopapular rash at 24 µg/kg, G3 IRR at 63µg/kg. No G ≥ 4 AEs occurred. Infusion-Related Reactions in 3 pts (G1, G2, and G3) and Cytokine Release Syndrome (G1 [2 pts] at both 32 and 42µg/kg and G2 [1 pt] at 16µg/kg) occurred. Conclusions: MT-6402 utilizes three PD-L1-targeted and unique MOAs: direct cell-kill, reduced immunosuppression, and increased immunorecognition. As of Feb 2023, 5 dose cohorts have completed. MT-6402 was well tolerated without CLS or payload-derived toxicity as is observed with traditional immunotoxins and ADCs, respectively. A PR in 1 pt with CPI-refractory NPC (CPS 2%, CMV^-) and regression of osseous metastases in a pt with NSCLC (TPS 80%, HLA-A*02/CMV⁺) following disease progression on CPI occurred. These results show MT-6402 monotherapy activity though unique MOAs and provide rationale for MT-6402 dose expansion. Clinical trial information: NCT04795713.