Some tumours, such as glioblastoma, are poorly infiltrated by immune cells and are defined as ‘cold’. Two phase I studies, recently published in Nature, show that the administration of personalized vaccines to newly diagnosed glioblastoma patients generates tumour-reactive T cells that infiltrate glioblastomas, turning them into ‘hot’ tumours potentially susceptible to further immunotherapy approaches.
Glioblastomas are characterized by a low mutational load and are estimated to contain few non-synonymous mutations, of which only a minority are processed to human leukocyte antigen (HLA)-presented neoepitopes that have the potential to induce a T cell response. The lack of antigenic epitopes is thought to be a major factor limiting glioblastoma immunogenicity. Therefore, vaccines targeting tumour-specific epitopes could unleash an immune response.
Keskin et al. designed a personalized vaccine strategy based on the identification of neoantigens in individual patients by comparing whole-exome sequencing data from the surgically resected tumour with the data from matched normal cells. They identified the coding mutations and, for each patient vaccine, selected a pool of 7–20 peptides representing actionable neoepitopes predicted to bind with high affinity to the HLA class I molecules of each patient.
A similar multi-epitope-based personalized vaccine was engineered by Hilf et al. in their study, although they targeted both neoantigens and unmutated tumour-specific antigens to increase the number of actionable epitopes. Neoantigens were selected using a protocol similar to that described by Keskin et al. The unmutated antigens were selected from a common pool of glioblastoma-specific HLA-bound peptides. For each patient, the unmutated peptides were ranked based on individual HLA immunopeptidome data and pre-vaccine T cell reactivity. Patients were vaccinated with a pool of 9 unmutated peptides (APVAC1) followed by a 20-peptide pool preferentially targeting neoantigens (APVAC2).
In the Keskin et al. study, eight patients with glioblastoma were vaccinated and five patients received both a priming and a booster vaccination. The two patients who did not receive the corticosteroid dexamethasone to treat side effects generated robust circulating T cell responses against multiple immunizing peptides. The response included both CD8+ and CD4+ T cells that were enriched in a memory phenotype. Surgery post-vaccination showed a significant increase in tumour-infiltrating T cells. Analysis of T cell receptor (TCR)-repertoire sequences demonstrated clonal expansion of neoantigen-reactive T cells in the tumour identical to circulating T cells, suggesting successful trafficking of vaccine-induced T cells to the tumour site. However, these infiltrating T cells also expressed markers of exhaustion, potentially explaining why all of the patients eventually died of progressive disease.
Hilf et al. treated 15 patients with glioblastoma, of which 11 received both the APVAC1 and APVAC2 vaccines. Analysis of the circulating immune response showed that most of the patients developed an increased number of CD8+ T cells reactive to at least one unmutated immunizing peptide that was accompanied by a shift to a memory phenotype. Most patients also developed a neoepitope-specific response that was, however, predominantly a CD4+ T cell response of T helper 1 type. Analysis of the tumour-infiltrating lymphocytes in one responding patient at relapse surgery post-vaccination showed higher T cell infiltration, a favourable CD8+:regulatory T (Treg) cell ratio and CD4+ T cell reactivity against one immunizing peptide. The median overall survival in this study was 29 months, suggesting a potential clinical benefit over other available options.
These studies show that, through personalized vaccines, cold tumours characterized by a low mutational burden can be successfully infiltrated by antigen-specific T cells that have the potential to kill cancer cells. However, once tumour-reactive T cells are brought into place, further treatments might be necessary to remove the inhibitory pressure exerted by the tumour microenvironment in order to produce a lasting clinical benefit.
Hilf, N. et al. Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 565, 240–245 (2019)
Keskin, D. B. et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565, 234–239 (2019)
About this article
Cite this article
Baratta, M.G. Glioblastoma is ‘hot’ for personalized vaccines. Nat Rev Cancer 19, 129 (2019). https://doi.org/10.1038/s41568-019-0118-8
Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology (2019)