Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma
Nature Medicine volume 27, pages515–525 (2021)
Zhuting Hu, Donna E. Leet, Rosa L. Allesøe, Giacomo Oliveira, Shuqiang Li, Adrienne M. Luoma, Jinyan Liu, Juliet Forman, Teddy Huang, J. Bryan Iorgulescu, Rebecca Holden, Siranush Sarkizova, Satyen H. Gohil, Robert A. Redd, Jing Sun, Liudmila Elagina, Anita Giobbie-Hurder, Wandi Zhang, Lauren Peter, Zoe Ciantra, Scott Rodig, Oriol Olive, Keerthi Shetty, Jason Pyrdol, Mohamed Uduman, Patrick C. Lee, Pavan Bachireddy, Elizabeth I. Buchbinder, Charles H. Yoon, Donna Neuberg, Bradley L. Pentelute, Nir Hacohen, Kenneth J. Livak, Sachet A. Shukla, Lars Rønn Olsen, Dan H. Barouch, Kai W. Wucherpfennig, Edward F. Fritsch, Derin B. Keskin, Catherine J. Wu & Patrick A. Ott
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.