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

Abstract

To evaluate safety and immunogenicity of intramuscularly delivered personalized neoantigen synthetic long peptide (SLP) vaccines in patients with advanced solid tumors. In this Phase I trial, 12 patients with advanced melanoma (n=9) or renal cell carcinoma (n=3) who lacked access to further reimbursed standard therapies at enrollment 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. 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, which were detectable as early as one week post-vaccination in most patients. On average, 53% 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 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. 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.