Targeting Neoantigens in Glioblastoma

Johanns, Tanner M.; Bowman-Kirigin, Jay A.; Liu, Connor; Dunn, Gavin P.

doi:10.1093/neuros/nyx321

Cited by 26 publications

(20 citation statements)

References 115 publications

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“…95 It was previously hypothesised that this hypermutant cohort may be more responsive to immune checkpoint blockade, 96 due to their neo-antigen load and antigen-targeting T cells. 97 Whilst IDH-wt GBM displays particularly low neo-antigen concentrations contributing to immunotherapy resistance, it was thought that inducing the mutational state in a subset of GBM patients might elicit an immune response to checkpoint inhibition. 97 It was also hypothesised that TMZ could induce this hypermutant state upon recurrence, with TMZ-induced hypermutations most commonly associated with MGMT methylated gliomas with IDH mutations.…”

Section: Ici Therapymentioning

confidence: 99%

“…97 Whilst IDH-wt GBM displays particularly low neo-antigen concentrations contributing to immunotherapy resistance, it was thought that inducing the mutational state in a subset of GBM patients might elicit an immune response to checkpoint inhibition. 97 It was also hypothesised that TMZ could induce this hypermutant state upon recurrence, with TMZ-induced hypermutations most commonly associated with MGMT methylated gliomas with IDH mutations. 97 Notwithstanding these assumptions, it has yet remained unclear whether high mutational burden may support a superior immune response to immune checkpoint blockade.…”

Section: Ici Therapymentioning

confidence: 99%

“…97 It was also hypothesised that TMZ could induce this hypermutant state upon recurrence, with TMZ-induced hypermutations most commonly associated with MGMT methylated gliomas with IDH mutations. 97 Notwithstanding these assumptions, it has yet remained unclear whether high mutational burden may support a superior immune response to immune checkpoint blockade. In an attempt to more accurately characterise the phenotypic and molecular features of hypermutated gliomas, Touat et al 98 recently showed that a low PD-1 blockade response rate was observed within a population of hypermutant gliomas that emerged following TMZ treatment.…”

Section: Ici Therapymentioning

confidence: 99%

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New hints towards a precision medicine strategy for IDH wild-type glioblastoma

et al. 2020

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Glioblastoma represents the most common primary malignancy of the central nervous system in adults and remains a largely incurable disease. The elucidation of disease subtypes based on mutational profiling, gene expression and DNA methylation has so far failed to translate into improved clinical outcomes. However, new knowledge emerging from the subtyping effort in the IDH-wild-type setting may provide directions for future precision therapies. Here, we review recent learnings in the field, and further consider how tumour microenvironment differences across subtypes may reveal novel contexts of vulnerability. We discuss recent treatment approaches and ongoing trials in the IDH-wildtype glioblastoma setting, and propose an integrated discovery stratagem incorporating multi-omics, single-cell technologies and computational approaches.

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Section: Ici Therapymentioning

confidence: 99%

Section: Ici Therapymentioning

confidence: 99%

Section: Ici Therapymentioning

confidence: 99%

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New hints towards a precision medicine strategy for IDH wild-type glioblastoma

et al. 2020

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“…The discovery of tumor-specific and tumor-associated antigens (TSA and TAA, respectively) have permitted development of a new array of therapeutic methods that selectively target gliomas and spare non-diseased cells of the CNS [ 36 , 37 ]. Many of these antigens are plasma membrane receptors [ 38 , 39 ]. Strategies to target TSA/TAA involve using antibodies to block ligand/receptor interactions, antibodies conjugated with modified versions of proteinaceous toxins or cytotoxic drugs or labels and nanoparticles or liposomes loaded with drugs that selectively target glioma TSA/TAA [ 40 , 41 ].…”

Section: Targeted Therapies For Gliomasmentioning

confidence: 99%

Receptor-Targeted Glial Brain Tumor Therapies

Sharma

Debinski

2018

IJMS

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Among primary brain tumors, malignant gliomas are notably difficult to manage. The higher-grade tumors represent an unmet need in medicine. There have been extensive efforts to implement receptor-targeted therapeutic approaches directed against gliomas. These approaches include immunotherapies, such as vaccines, adoptive immunotherapy, and passive immunotherapy. Targeted cytotoxic radio energy and pro-drug activation have been designed specifically for brain tumors. The field of targeting through receptors progressed significantly with the discovery of an interleukin 13 receptor alpha 2 (IL-13RA2) as a tumor-associated receptor over-expressed in most patients with glioblastoma (GBM) but not in normal brain. IL-13RA2 has been exploited in novel experimental therapies with very encouraging clinical responses. Other receptors are specifically over-expressed in many patients with GBM, such as EphA2 and EphA3 receptors, among others. These findings are important in view of the heterogeneity of GBM tumors and multiple tumor compartments responsible for tumor progression and resistance to therapies. The combined targeting of multiple receptors in different tumor compartments should be a preferred way to design novel receptor-targeted therapeutic approaches in gliomas.

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“…1 Due to their tumor-restricted expression, neoantigens represent compelling targets for personalized cancer vaccines. [2][3][4][5][6][7] In preclinical tumor models, polyvalent neoantigen vaccines can be therapeutically effective. 8,9 Furthermore, neoantigen-based vaccines can elicit immune responses in patients, 2,6,7 although these studies have been restricted to melanoma, which generally possesses high mutational burdens, and therefore, potentially contains a high number of candidate neoantigens.…”

Section: Introductionmentioning

confidence: 99%

Detection of neoantigen-specific T cells following a personalized vaccine in a patient with glioblastoma

et al. 2019

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Neoantigens represent promising targets for personalized cancer vaccine strategies. However, the feasibility of this approach in lower mutational burden tumors like glioblastoma (GBM) remains unknown. We have previously reported the use of an immunogenomics pipeline to identify candidate neoantigens in preclinical models of GBM. Here, we report the application of the same immunogenomics pipeline to identify candidate neoantigens and guide screening for neoantigen-specific T cell responses in a patient with GBM treated with a personalized synthetic long peptide vaccine following autologous tumor lysate DC vaccination. Following vaccination, reactivity to three HLA class I-and five HLA class II-restricted candidate neoantigens were detected by IFN-γ ELISPOT in peripheral blood. A similar pattern of reactivity was observed among isolated post-treatment tumor-infiltrating lymphocytes. Genomic analysis of pre-and post-treatment GBM reflected clonal remodeling. These data demonstrate the feasibility and translational potential of a therapeutic neoantigen-based vaccine approach in patients with primary CNS tumors.

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Targeting Neoantigens in Glioblastoma

Cited by 26 publications

References 115 publications

New hints towards a precision medicine strategy for IDH wild-type glioblastoma

New hints towards a precision medicine strategy for IDH wild-type glioblastoma

Receptor-Targeted Glial Brain Tumor Therapies

Detection of neoantigen-specific T cells following a personalized vaccine in a patient with glioblastoma

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