Neoantigen Peptide Vaccine(Fred Hutchinson Cancer Research Center)

Neoantigens are tumor-specific antigens that emerge due to gene mutations in tumor cells, and are highly antigenic epitopes that escape central immune tolerance in the thymus, making cancer vaccine therapy a desirable option.

Tumor neoantigens were predicted in 17 patients with advanced cancer. They were resistant to the standard treatment regime, and their synthetic peptides were pulsed to the patient's monocyte-derived dendritic cells (DCs), and administered to the patient's lymph nodes via ultrasound.

Some patients showed sustained tumor shrinkage after this treatment, while some did not respond, showing no ELISpot reaction. Although the number of mutations and the predicted neoantigen epitopes differed between patients, the clinical effect depended more on the presence or absence of an immune response after vaccination rather than the number of neoantigens.

Intranodal neoantigen peptide-pulsed DC vaccine administration therapy has clinical and immunological efficacy and safety.

Personal neoantigen vaccines have been envisioned as an effective approach to induce, amplify and diversify antitumor T cell responses. To define the long-term effects of such a vaccine, we evaluated the clinical outcome and circulating immune responses of eight patients with surgically resected stage IIIB/C or IVM1a/b melanoma, at a median of almost 4 years after treatment with NeoVax, a long-peptide vaccine targeting up to 20 personal neoantigens per patient ( NCT01970358 ). All patients were alive and six were without evidence of active disease. We observed long-term persistence of neoantigen-specific T cell responses following vaccination, with ex vivo detection of neoantigen-specific T cells exhibiting a memory phenotype. We also found diversification of neoantigen-specific T cell clones over time, with emergence of multiple T cell receptor clonotypes exhibiting distinct functional avidities. Furthermore, we detected evidence of tumor infiltration by neoantigen-specific T cell clones after vaccination and epitope spreading, suggesting on-target vaccine-induced tumor cell killing. Personal neoantigen peptide vaccines thus induce T cell responses that persist over years and broaden the spectrum of tumor-specific cytotoxicity in patients with melanoma.