|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Keskin, DB, Anandappa, AJ, Sun, J, Tirosh, I, Mathewson, ND, Li, S, Oliveira, G, Giobbie-Hurder, A, Felt, K, Gjini, E, Shukla, SA, Hu, Z, Li, L, Le, PM, Allesøe, RL, Richman, AR, Kowalczyk, MS, Abdelrahman, S, Geduldig, JE, Charbonneau, S, Pelton, K, J Iorgulescu, B, Elagina, L, Zhang, W, Olive, O, McCluskey, C, Olsen, LR, Stevens, J, Lane, WJ, Salazar, AM, Daley, H, Wen, PY, E Chiocca, A, Harden, M, Lennon, NJ, Gabriel, S, Getz, G, Lander, ES, Regev, A, Ritz, J, Neuberg, D, Rodig, SJ, Ligon, KL, Suvà, ML, Wucherpfennig, KW, Hacohen, N, Fritsch, EF, Livak, KJ, Ott, PA, Wu, CJ, Reardon, DA|
|Date Published||2019 Jan|
Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses and can function as bona fide antigens that facilitate tumour rejection. Here we demonstrate that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma, is feasible for tumours such as glioblastoma, which typically have a relatively low mutation load and an immunologically 'cold' tumour microenvironment. We used personalized neoantigen-targeting vaccines to immunize patients newly diagnosed with glioblastoma following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone-a highly potent corticosteroid that is frequently prescribed to treat cerebral oedema in patients with glioblastoma-generated circulating polyfunctional neoantigen-specific CD4 and CD8 T cell responses that were enriched in a memory phenotype and showed an increase in the number of tumour-infiltrating T cells. Using single-cell T cell receptor analysis, we provide evidence that neoantigen-specific T cells from the peripheral blood can migrate into an intracranial glioblastoma tumour. Neoantigen-targeting vaccines thus have the potential to favourably alter the immune milieu of glioblastoma.