Immunostimulatory and Immunodynamic Modeling Analysis to Determine a Plausible Starting Dose of <scp>mRNA</scp> ‐4359 for Use in First‐In‐Human Trials

The investigational antigen-specific immunotherapy mRNA-4359 is a lipid nanoparticle-encapsulated mRNA-based immunotherapy that encodes for the immunogenic indoleamine 2,3-dioxygenase (IDO) and programmed death-ligand 1 (PD-L1) antigens. An ongoing first-in-human (FIH) phase 1/2 clinical trial (NCT05533697) will evaluate the safety and antitumor activity of mRNA-4359 when administered alone and in combination with the anti-programmed death-1 agent pembrolizumab in participants with advanced solid tumors. The current analysis applied a novel immunostimulatory/immunodynamic (IS/ID) modeling approach to determine a plausible starting dose of mRNA-4359 for the FIH trial. The model used for the FIH dose prediction was calibrated to previously published clinical trial data obtained for an immunomodulatory peptide-based vaccine activating IDO- and PD-L1-specific T cells in patients with metastatic melanoma. The analysis found that a 180 μg dose of mRNA-4359 would possibly elicit a T-cell response similar to a 200 μg dose of the peptide-based vaccine with a range of 45-360 μg, assuming a potential 4-fold higher to 2-fold lower efficiency (the ability to elicit IFN-γ secreting T cells, indicative of cytotoxic potential). Model simulations further predicted that a 15-cycle every 3 weeks regimen of mRNA-4359 could be expected to provide longer responses than other feasible simulated regimens. Finally, the IS/ID modeling analysis determined that a 100 μg dose of mRNA-4359 would be the most appropriate starting dose for FIH trials. The described approach represents a unique application of IS/ID modeling to determine a therapeutically relevant FIH starting dose in the absence of supporting preclinical animal data.