Background: V-domain Ig Suppressor of T-cell Activation (VISTA), is an immune checkpoint regulator found on tumor, myeloid, and other immune cells. Its presence has been shown to enhance tumor growth, create an immunosuppressive microenvironment, and may potentially contribute to developing resistance to anti-CTLA-4 and anti-PD-1/PD-L1 therapies. Therefore, VISTA represents a promising therapeutic target. HMBD-002, a non-depleting, high-affinity IgG4 monoclonal antibody against VISTA, has demonstrated significant inhibition of tumor growth in preclinical studies, both as a monotherapy and in combination with pembrolizumab. HMBD-002 acts by increasing T-cell activity and reprogramming the suppressive tumor microenvironment to a proinflammatory antitumor phenotype. Cancer types including triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC), which exhibit high expression levels of VISTA in the TME, provide a rational basis for exploring these indications in clinical studies. Methods: This phase 1/2, open-label, multi-center trial is being conducted in two parts to evaluate the safety, pharmacokinetics, and antitumor activity of HMBD-002, an IgG4 monoclonal antibody targeting VISTA, as a monotherapy and in combination with pembrolizumab. The dose-escalation stage (Part 1) will follow a standard 3 + 3 study design with weekly dosing and adaptive dose-escalation increments to determine the recommended phase 2 dose (RP2D) for subsequent disease-directed studies. Monotherapy escalation cohorts 1-4 have been completed without dose-limiting toxicities (DLTs). The dose-expansion stage (Part 2) will evaluate the antitumor activity of HMBD-002 alone and combined with pembrolizumab in patients with TNBC and NSCLC, as well as a wide range of VISTA-expressing malignancies. Exploratory analyses will be conducted to assess treatment-induced immunological changes both systemically and within the tumor microenvironment. Longitudinal blood samples will be evaluated using single-cell mass cytometry (CYTOF) and multiplex cytokine analysis. Pre and on-treatment tumor tissue samples will be assessed for VISTA & PD-L1 expression using IHC. Additionally, tumor tissues will be evaluated using multiplex immunofluorescence, and gene-expression profiling. Biomarker correlations with clinical outcomes may lead to the identification of predictive markers of response to HMBD-002. Clinical trial information: NCT05082610.