IMPACT - Phase Ib Trial of Intramuscular Personalized Neoantigen Synthetic Long Peptide Vaccines in Patients with Advanced Melanoma and Renal Cell Carcinoma

Abstract Purpose To evaluate safety and immunogenicity of intramuscularly delivered personalized neoantigen synthetic long peptide (SLP) vaccines in patients with advanced solid tumors. Patients and Methods In this Phase I trial, 12 patients with advanced melanoma (n=9) or renal cell carcinoma (n=3) who could no longer access further standard treatments received intramuscular neoantigen SLP vaccines with poly-ICLC. Each vaccine contained ∼20 predicted neoantigen peptides. Adverse events were monitored throughout vaccination and follow-up. Immune profiling was performed at baseline and predefined post-vaccination time points. Results Intramuscular neoantigen vaccination was well tolerated, with only grade 1–2 local pain or fever and no immune-mediated toxicities. All participants developed de novo T-cell responses, detectable within one week. On average, 46% of peptides per patient were immunogenic, inducing both CD8⁺ and CD4⁺ neoantigen-specific responses. Patients previously treated with immune checkpoint inhibitors (ICIs) had higher baseline immunity but achieved comparable post-vaccination responses to ICI-naïve patients. IFN-γ–dominant CD8⁺ and TNF-α–dominant CD4⁺ responses were observed, along with increased effector memory differentiation. Two patients with higher CD8⁺ TEMRA proportions were the longest survivors. Tumor biopsies revealed enhanced CD8⁺ infiltration, and epitope spreading occurred in one of two evaluable cases. Analysis of 239 peptides showed greater immunogenicity for dual MHC I/II–binding, cysteine-containing, and in-frame indel- or low-VAF–derived mutations, while proline substitutions reduced responses. Conclusions Intramuscular neoantigen SLP vaccination with poly-ICLC is safe and induces rapid, mutation-specific T-cell immunity with robust CD8⁺ effector responses. These findings support intramuscular administration as a promising strategy for peptide-based cancer vaccines. Translational relevance Personalized neoantigen vaccines offer a promising strategy to enhance tumor-specific immunity, but most prior studies using intradermal or subcutaneous delivery have shown limited induction of cytotoxic CD8⁺ T cells. This study demonstrates that intramuscular administration of personalized neoantigen synthetic long peptide vaccines with poly-ICLC is safe, feasible, and capable of eliciting rapid, mutation-specific CD4⁺ and CD8⁺ T-cell responses in patients with advanced melanoma and renal cell carcinoma. Vaccine-induced immunity was dominated by IFN-γ–producing cells and accompanied by a shift toward effector memory phenotypes. In selected cases, post-treatment tumor biopsies revealed increased CD8⁺ infiltration. These findings support intramuscular delivery as a practical and effective platform for neoantigen-based cancer vaccine.