Background: mRNA-4359 is a lipid nanoparticle encapsulated mRNA-based cancer vaccine encoding for concatemerized program death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) antigens given as an intramuscular injection. These proteins are found across a wide range of cancer types. PD-L1 is a cell surface receptor expressed on both tumor and regulatory immune cells and functions as a checkpoint to inhibit T cell function, while IDO1 is an L-tryptophan metabolizing enzyme involved in T cell suppression and immune tolerance. Both are thought to impart an inhibitory tumor microenvironment which allows tumor cells to escape immune monitoring and clearance. T cells that can target PD-L1 and IDO1 are known to pre-exist in cancer patients and a recent study leveraging a peptide-based vaccine approach demonstrated they can be induced to elicit clinically meaningful and durable tumor responses in patients with metastatic melanoma when combined with PD-1 inhibition. mRNA-4359 encodes immunogenic peptides proposed to generate anti-PD-L1/IDO1-specific T-cells to kill immunosuppressive regulatory cells as well as cancer cells which express those antigens and thus tip the balance towards an inflammatory and/or immune permissive tumor microenvironment. Additionally, combination with checkpoint inhibition may further amplify this anti-tumor immunostimulatory effect, resulting in superior clinical outcomes. Methods: The primary objective of this first in human, open label Phase 1/2 study is to assess safety and tolerability, with secondary objectives to measure T cell profile changes and initial anti-tumor activity. Arm 1a entails dose escalation of mRNA-4359 monotherapy with dose levels guided by a modified continual reassessment method in participants with locally advanced/metastatic cancers, including cutaneous melanoma, non-small cell lung cancer (NSCLC), non-muscle invasive bladder cancer, head/ neck squamous cell carcinoma, microsatellite stable colorectal cancer, basal cell carcinoma or triple negative breast cancer. Arm 1b will be dose confirmatory and will run concurrently with a pharmacodynamic arm; both will assess mRNA-4359 in combination with pembrolizumab in patients with primary/secondary checkpoint inhibitor refractory locally advanced/metastatic melanoma or NSCLC. The totality of available data from these arms will be used to support determination of a recommended phase 2 dose. Arm 2 includes two single arm expansion cohorts evaluating mRNA-4359 in combination with pembrolizumab therapy in patients who have not received any prior therapy for their cancer in this setting of locally advanced/metastatic melanoma (Cohort 1) or locally advanced/metastatic NSCLC with PD-L1 TPS of ≥ 1% (Cohort 2). Study enrollment into Arm 1a has commenced in the United States and Australia with plans to open sites in Europe later in 2023. Clinical trial information: NCT05533697.