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Background Personalized tumor vaccines directed against cancer-specific neoantigens have demonstrated activity in the adjuvant setting in melanoma. It is unknown whether such an approach can overcome immune evasion in patients with PD-1 inhibitor-refractory metastatic melanoma.Methods In this phase I clinical trial, we treated patients with PD-1 inhibitor-refractory metastatic melanoma using PNV-21, a novel personalized neoantigen vaccine composed of up to 20 neoantigen peptides. The latter were identified from whole-exome and RNA sequencing of each patient‘s tumor. PNV-21 was administered intramuscularly (IM) every four weeks for up to six doses in combination with the adjuvant Poly-ICLC (TLR-3 ligand). Patients also received IM Poly-ICLC weekly during non-vaccine weeks and intravenous nivolumab (480 mg) every four weeks. The primary endpoint was safety, and a secondary endpoint was best overall response. Serial blood samples and tumor biopsies were collected. ELISpot, ICS, FACS and IHC were used to assess vaccine-induced immune response.Results All eight enrolled patients received at least two doses of PNV-21, and three patients completed all six doses. All treatment-related adverse events were CTCAE grade ≤2, including injection site reactions (75%) and flu-like symptoms (75%). No patients discontinued treatment due to toxicity. The objective response rate was 25% (2/8) with one patient with bulky metastatic disease, previously progressing on anti-PD-1 and anti-CTLA-4 therapy, achieved a pathological complete response for 15 months ( figure 1), while another had a partial response. Two additional patients had stable disease, and the remaining four had progressive disease as best response (figure 2). Vaccine antigen-specific CD8+ T cell responses to 37 antigens (0 to 19 per patient, 5/6 patients) and CD4+ T cell responses to 47 antigens (3 to 16 per patient) were detected in peripheral blood in six evaluable patients. Increased CD8+ T cell tumor infiltration post-vaccination was observed in five of six evaluable patients. Tumor-infiltrating CD8+ T cells specific to both vaccine-derived and other melanoma antigens were identified and characterized via single-cell RNA sequencing. Increases in tumor immune infiltration was observed in both responding and non-responding patients.Conclusions PNV-21, a personalized neoantigen peptide vaccine, combined with nivolumab and weekly Poly-ICLC, was demonstrated to be well tolerated and safe. Furthermore, the treatment led to anti-tumor immune activation and objective responses in heavily pretreated patients with metastatic melanoma. Vaccine-induced immune responses were detectable in patients with and without objective clinical benefit.Acknowledgements Funding for this trial was provided by Amazon, and we would llike to thank patients and their families.Ethics Approval The study was approved by the Fred Hutchinson Cancer Center IRB (approval number RG1121642).Abstract 608 Figure 1Regression of large tumor following vaccination in patient 6, residual tumor negative for melanoma by pathology of biopsy at 6 monthsAbstract 608 Figure 2RECIST changes from baseline, numbers refer to patient identifier