Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial

Derin B. Keskin, Annabelle J. Anandappa, Jing Sun, Itay Tirosh, Nathan D. Mathewson, Shuqiang Li, Giacomo Oliveira, Anita Giobbie-Hurder, Kristen Felt, Evisa Gjini, Sachet A. Shukla, Zhuting Hu, Letitia Li, Phuong M. Le, Rosa Lundbye Allesøe, Alyssa R. Richman, Monika S Kowalczyk, Sara Abdelrahman, Jack E. Geduldig, Sarah CharbonneauKristine Pelton, J. Bryan Iorgulescu, Liudmila Elagina, Wandi Zhang, Oriol Olive, Christine McCluskey, Lars Rønn Olsen, Jonathan Stevens, William J. Lane, Andres M. Salazar, Heather Daley, Patrick Y. Wen, E. Antonio Chiocca, Maegan Harden, Niall J. Lennon, Stacey Gabriel, Gad Getz, Eric S. Lander, Aviv Regev, Jerome Ritz, Donna Neuberg, Scott J. Rodig, Keith L. Ligon, Mario L. Suvà, Kai W. Wucherpfennig, Nir Hacohen, Edward F. Fritsch, Kenneth J Livak, Patrick A Ott, Catherine J Wu, David A. Reardon

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    Abstract

    Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses1,2 and can function as bona fide antigens that facilitate tumour rejection3. Here we demonstrate that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma4-6, is feasible for tumours such as glioblastoma, which typically have a relatively low mutation load1,7 and an immunologically 'cold' tumour microenvironment8. 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.
    Original languageEnglish
    JournalNature
    Volume565
    Pages (from-to)234-239
    Number of pages4
    ISSN0028-0836
    DOIs
    Publication statusPublished - 2018

    Cite this

    Keskin, D. B., Anandappa, A. J., Sun, J., Tirosh, I., Mathewson, N. D., Li, S., Oliveira, G., Giobbie-Hurder, A., Felt, K., Gjini, E., Shukla, S. A., Hu, Z., Li, L., Le, P. M., Allesøe, R. L., Richman, A. R., Kowalczyk, M. S., Abdelrahman, S., Geduldig, J. E., ... Reardon, D. A. (2018). Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature, 565, 234-239. https://doi.org/10.1038/s41586-018-0792-9