2018
DOI: 10.1038/s41586-018-0792-9
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Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial

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 immunolog… Show more

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Cited by 1,062 publications
(970 citation statements)
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“…Personalized NeoAg vaccines tested thus far have demonstrated cautiously encouraging clinical responses that can be improved to provide a less costly alternative to ACT with either TIL or engineered T cells. RNA‐ and peptide‐based NeoAg vaccines in melanoma and glioblastoma have induced the expansion of T cells recognizing targeted epitopes 44,111,112 . Patients receiving RNA‐based multiepitope vaccines experienced significantly reduced incidence of metastatic events compared to pretreatment 112 .…”
Section: Considerations For Neoag‐specific Therapiesmentioning
confidence: 99%
“…Personalized NeoAg vaccines tested thus far have demonstrated cautiously encouraging clinical responses that can be improved to provide a less costly alternative to ACT with either TIL or engineered T cells. RNA‐ and peptide‐based NeoAg vaccines in melanoma and glioblastoma have induced the expansion of T cells recognizing targeted epitopes 44,111,112 . Patients receiving RNA‐based multiepitope vaccines experienced significantly reduced incidence of metastatic events compared to pretreatment 112 .…”
Section: Considerations For Neoag‐specific Therapiesmentioning
confidence: 99%
“…More promisingly, two independent phase I clinical trials evaluating personalised neoantigen vaccines triggering both CD4 and CD8 T‐cell activation showed encouraging results in patients with melanoma . Neoantigen vaccination has also been shown to effectively elicit T‐cell responses in patients with glioblastoma, which is classified as an immunologically cold tumor characterised by few infiltrating immune cells and a relatively low mutational burden . Furthermore, mounting evidence demonstrates that the load and quality of neoantigens are biomarkers for predicting the efficacy of checkpoint inhibitor‐based cancer immunotherapy .…”
Section: Introductionmentioning
confidence: 99%
“…2,3 Neoantigen vaccination has also been shown to effectively elicit T-cell responses in patients with glioblastoma, which is classified as an immunologically cold tumor characterised by few infiltrating immune cells and a relatively low mutational burden. 4 Furthermore, mounting evidence demonstrates that the load and quality of neoantigens are biomarkers for predicting the efficacy of checkpoint inhibitorbased cancer immunotherapy. [5][6][7] Therefore, the identification of immunogenic neoantigens has promising clinical implications for cancer immunotherapy.…”
Section: Introductionmentioning
confidence: 99%
“…Dex is also highly toxic to immune cells including T cells, which may limit the CAR T cell efficacy. In particular, Dex is known to inhibit priming of T cell immune response by dendritic cells, and was shown to be deleterious to vaccine trials for GBM at very low levels . In preclinical mouse models, intratumorally delivered CAR T cells were functional with low‐levels of Dex (1 and 0.2 mg/kg), but were strongly suppressed by high levels (5 mg/kg) .…”
Section: From Bench To Bedside: Clinical Trial Considerationsmentioning
confidence: 99%
“…Approaches to stimulate or enhance endogenous T cell immune responses to treat brain tumors are showing evidence of bioactivity, including clinical studies of tumor neoantigen vaccines, oncolytic viruses, and immune checkpoint inhibitors (ICIs) . The engagement of checkpoint receptors such as programmed cell death protein‐1 (PD‐1) and cytotoxic T‐lymphocyte‐associated antigen 4 (CTLA4) dampen anti‐tumor immune responses, and these checkpoint pathways have emerged as critical drivers of immunosuppression in solid cancers .…”
Section: Introductionmentioning
confidence: 99%