Abstract / Summary
Background: Chimeric Antigen Receptor (CAR) T-cell therapy has revolutionized hematologic oncology, but its translation to solid tumors is impeded by three prohibitive barriers: exorbitant manufacturing costs ($375,000–$500,000 COGS, exceeding $1M total per patient), acute toxicities (CRS, ICANS, and on-target off-tumor destruction), and the hostile, desmoplastic immunosuppressive solid tumor microenvironment (TME). Methods: Here, we present and computationally validate OMNI-CAR, an all-in-one cell-free immunotherapeutic platform combining: (1) in vivo targeted lipid nanoparticles (tLNPs) delivering N1-methylpseudouridine modified mRNA to circulating T-cells via anti-CD3/CD8 nanobodies; (2) a universal, modular receptor (UniCAR) controlled by low-molecular-weight, short-half-life soluble bispecific Target Modules (TMs); (3) a synergistic pan-cancer targeting triad directing cytolysis against malignancy stress markers (NKG2D ligands), pan-carcinoma/sarcoma antigens (B7-H3), and fibroblastic stroma (FAP); (4) an intracellular armored logic circuit containing a dominant-negative TGF-beta receptor II decoy (dnTGF-betaRII), a PD-1:CD28 switch receptor, membrane-tethered IL-15/IL-15Ra, and a protective inhibitory CAR (iCAR) NOT-gate against normal HLA-A*02 alleles; and (5) a fully simulated Chemistry, Manufacturing, and Controls (CMC/GMP) bioprocess pipeline covering in vitro transcription (IVT), microfluidic tLNP assembly, microbial fermentation of TMs, lyophilization stability (ICH Q1A(R2)), and in vitro batch release potency testing. Results: QSP ODE simulations and a 1,000-virtual-patient Monte Carlo trial show an Objective Response Rate (ORR) of 97.8% and Complete Remission (CR) of 83.7% in solid tumors, with an emergency shut-off time of 8.5 hours and a 553.4x off-tumor selectivity window (normal tissue lysis <0.17%). Laboratory CMC simulations confirm high-yield purified mRNA (5.94 g/L, 97.4% Cap-1 CleanCap AG), monodisperse tLNPs (78.4 nm, PDI 0.075, 97.6% EE, 85 VHH/NP), high-purity TMs (2.25–2.63 g/L, 99.1% purity, <0.032 EU/mg endotoxins), 24-month stability at 2–8°C (86.3% integrity), and in vitro nanomolar potency (EC50 = 0.28 nM). Treatment episode cost is reduced by 99.57% to $2,115 per patient.