Effective anti-tumor immunity in humans has been associated with the presence of T cells directed at cancer neoantigens1, which are T cell epitopes with tumor-specific expression arising from non-silent somatic mutations. They are highly immunogenic because they are not expressed in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumor immune response2, their systematic discovery and evaluation only became feasible with the recent availability of massively-parallel sequencing for detection of all coding mutations within tumors, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous HLA molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T cell populations and induce a broader repertoire of new T cell specificities in cancer patients, tipping the intra-tumoral balance in favor of enhanced tumor control. Here we demonstrate the feasibility, safety and immunogenicity of a vaccine that targets up to 20 predicted personal tumor neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%), respectively, of the 97 unique neoantigens used across patients. These T cells discriminated mutated from wildtype antigens, and in some cases, directly recognized autologous tumor. Of 6 vaccinated patients, 4 had no recurrence at 25 months post-vaccination, while 2 with progressive disease were subsequently treated with anti-PD-1 therapy and experienced complete tumor regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint therapies.

Background In a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab demonstrated a high objective response rate, including complete responses in patients with advanced melanoma. Methods In this double-blind study, 142 treatment-naïve patients with metastatic melanoma were randomized 2:1 to receive ipilimumab 3 mg/kg combined with either nivolumab 1 mg/kg or placebo every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg or placebo every 2 weeks until disease progression. The primary endpoint was investigator-assessed objective response in BRAF wild-type patients. Results Among BRAF wild-type patients, the confirmed objective response rate was 61.1% (44/72) in the nivolumab and ipilimumab combination group versus 10.8% (4/37) in the ipilimumab monotherapy group (P<0.001), with complete responses reported in 16 (22.2%) patients in the combination group; none in the ipilimumab group. Median duration of response was not reached with either treatment. Median progression-free survival was not reached for the combination versus 4.4 months for ipilimumab monotherapy (hazard ratio 0.40, 95% CI 0.23 to 0.68; P<0.001). Similar results for response and progression-free survival were also observed in 33 BRAF mutation-positive patients. Grade 3–4 drug-related adverse events were reported in 54.3% of patients receiving the combination compared with 23.9% with ipilimumab monotherapy. Select adverse events of immunological etiology were consistent with phase 1 reports, and most resolved with immune-modulating medication. Conclusion Nivolumab combined with ipilimumab significantly improved objective response rate and progression-free survival compared with ipilimumab monotherapy in treatment-naïve patients with advanced melanoma, and had a manageable safety profile. (ClinicalTrials.gov number, NCT01927419)