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

PURPOSE: To evaluate the 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 lacked access to further reimbursed standard therapies at enrollment received intramuscular neoantigen SLP vaccines with Polyinosinic-Polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC). Each vaccine contained about 20 predicted neoantigen peptides. Adverse events were monitored throughout vaccination and follow-up. Immune profiling was performed at baseline and predefined postvaccination time points.

RESULTS

Intramuscular neoantigen vaccination was well tolerated, with only grade 1 to 2 local pain or fever and no immune-mediated toxicities. All participants developed de novo T-cell responses, which were detectable as early as 1 week after 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 (ICI) had higher baseline immunity but achieved comparable postvaccination responses to ICI-naïve patients. IFNγ-dominant CD8+ and TNFα-dominant CD4+ responses were observed, along with increased effector memory differentiation. Two patients with higher CD8+ terminal effector memory RA (TEMRA) proportions were the longest survivors. Tumor biopsies revealed enhanced CD8+ infiltration, and epitope spreading occurred in two evaluable cases. An analysis of 239 peptides showed greater immunogenicity for dual MHC I/II-binding, cysteine-containing, in-frame insertions or deletions-derived or low variant allele frequency-derived mutations, whereas 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.