Integrating multisector molecular characterization into personalized peptide vaccine design for patients with newly diagnosed glioblastoma.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE238012 | GEO | 2024/04/12
REPOSITORIES: GEO
Similar Datasets
Project description:Incorporation of multisector sampling in glioblastoma increases the candidate pool of potentially targetable neoantigens that can be successfully developed into a peptide-based vaccine
2024-04-12 | GSE238010 | GEO
Project description:Personalized NeoAntigen Cancer Vaccine with RT for Newly Diagnosed Glioblastoma
| PRJNA429518 | ENA
Project description:Personalized NeoAntigen Cancer Vaccine with RT for Newly Diagnosed Glioblastoma
| PRJNA429519 | ENA
Project description:Abstract BACKGROUND Glioblastomas (GBM) are known for having a lower mutational burden than many other tumor types. Nevertheless, somatic variants that occur in GBM mutational processes may give rise to neoantigens, which can be targeted in a personalized genomic vaccine to elicit a patient-specific anti-tumor response. METHODS Normal and tumor DNA and tumor RNA are extracted from tumor specimens and PBMCs. Exome and RNA sequencing and HLA typing is performed for each patient. Neoantigens are identified using the OpenVax computational pipeline, which calls somatic variants in the DNA and prioritizes corresponding candidate neoantigens for vaccination based on tumor RNA expression and predicted MHC class I binding affinity for each of the patient’s HLA alleles. This work is the base for a phase I trial of personalized neoantigen vaccines in combination with Tumor Treating Fields for GBM (NCT03223103). RESULTS For each of the 9 patients enrolled in the trial, an average of 1005 somatic mutations were identified (range 299–2441), of which 118 were coding variants (range 52–198), 20 were coding and expressed in the tumor RNA (range 9–45), and 16 were coding, expressed and resulted in predicted MHC class I ligands (range 7–33). An average of 2.3% of all somatic variants identified in each tumor gave rise to predicted neoantigens. Sufficient numbers of neoantigens were identified in all tumor samples of the patients enrolled in the study. The overall somatic mutation landscape for the tumors revealed 4/9 PIK3R1 deletions, 2/9 IDH1 substitutions, as well as disruptions in PTEN, TP53, and ATRX, among others. CONCLUSIONS Identifying sufficient neoantigens for inclusion in the personalized genomic vaccine is computationally feasible despite a typically low GBM mutational burden. Driver and passenger mutations can be identified through the same computational pipeline utilized for other tumor types.
| S-EPMC7651423 | biostudies-literature
Project description:Glioblastoma (GBM) is a highly invasive brain tumor, whose cells infiltrate surrounding normal brain tissue beyond the lesion outlines visible in the current medical scans. These infiltrative cells are treated mainly by radiotherapy. Existing radiotherapy plans for brain tumors derive from population studies and scarcely account for patient-specific conditions. Here, we provide a Bayesian machine learning framework for the rational design of improved, personalized radiotherapy plans using mathematical modeling and patient multimodal medical scans. Our method, for the first time, integrates complementary information from high-resolution MRI scans and highly specific FET-PET metabolic maps to infer tumor cell density in GBM patients. The Bayesian framework quantifies imaging and modeling uncertainties and predicts patient-specific tumor cell density with credible intervals. The proposed methodology relies only on data acquired at a single time point and, thus, is applicable to standard clinical settings. An initial clinical population study shows that the radiotherapy plans generated from the inferred tumor cell infiltration maps spare more healthy tissue thereby reducing radiation toxicity while yielding comparable accuracy with standard radiotherapy protocols. Moreover, the inferred regions of high tumor cell densities coincide with the tumor radioresistant areas, providing guidance for personalized dose-escalation. The proposed integration of multimodal scans and mathematical modeling provides a robust, non-invasive tool to assist personalized radiotherapy design.
| S-EPMC7170051 | biostudies-literature
Project description:Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults with a dismal prognosis. We previously reported that vaccination with heat shock protein peptide complex-96 (HSPPC-96) improves survival in patients with newly diagnosed GBM (NCT02122822). Especially for patients with a strong antitumor immune response after vaccination, a durable survival benefit can be achieved. Here, we conducted T cell receptor (TCR) sequencing to retrospectively examine the TCR repertoires of tumor-infiltrating lymphocytes in long-term survivors (LTS) and short-term survivors (STS). We found that LTS exhibit lower TCR repertoire diversity compared with STS, indicating the prevalence of dominant TCR clones in LTS tumors. Accordingly, the LTS group showed increased inter-patient similarity, especially among high-frequency TCR clones, implying some of these dominant clones are shared among LTS. Indeed, we discovered four TCR clones significantly enriched in the LTS group: the presence of these clones has predictive value for stratifying patients prior to vaccination. Together, these findings uncover a group of preexisting TCR clones shared in LTS that can be utilized as candidate biomarkers to select GBM patients most likely to durably respond to HSPPC-96 treatment.
| S-EPMC7153824 | biostudies-literature
Project description:Glioblastoma is an aggressive and inevitably recurrent primary intra-axial brain tumor with a dismal prognosis. The current mainstay of treatment involves maximally safe surgical resection followed by radiotherapy over a 6-week period with concomitant temozolomide chemotherapy followed by temozolomide maintenance. This review provides a summary of the epidemiological, clinical, histologic and genetic characteristics of newly diagnosed disease as well as the current standard of care and potential future therapeutic prospects.
| S-EPMC7892469 | biostudies-literature
Project description:Glioblastoma is the most common primary brain tumor in adults. Despite current multimodality treatment including surgical resection and temozolomide-based chemoradiotherapy, median survival is only 14-16 months. Characterization of molecular alterations in glioblastoma has identified prognostic subgroups and therapeutic opportunities for clinical trials across glioblastoma subsets. Following a number of negative Phase III trials testing temozolomide dose intensification and angiogenesis inhibition, recent interim analysis data indicate survival prolongation with use of a device (Optune™) delivering alternating electrical field therapy in newly diagnosed glioblastoma patients. In this review, we present an overview of the data supporting the current standard of care and discuss novel experimental therapies in early and late phase clinical testing including devices, small molecule drugs, angiogenesis inhibitors, oncolytic virotherapy and immunotherapy.
| S-EPMC4976851 | biostudies-literature
Project description:PurposeGlioblastoma (GBM) shows frequent relapse and is highly resistant to treatment; therefore, it is considered fatal. Various vaccination protocols that have been tested in patients with GBM, which is the most common and aggressive primary brain tumor, have indicated safety and efficacy, to some extent, when used alone or in combination with standard of care. Recently, neoantigen-based personalized vaccines have shown tremendous immunogenicity and safety in GBM. We aimed to systematically review the medical literature for clinical trials to evaluate the efficacy and safety of neoantigen-based personalized vaccines for newly diagnosed GBM.MethodsWe conducted a literature search for clinical trials on PubMed, Cochrane Library, China National Knowledge Infrastructure, and ClinicalTrials.gov until March 20, 2021. The primary outcomes of interest were immunogenicity and safety of the therapy. Efficacy outcomes, such as progression-free survival and overall survival, were secondary outcomes of interest.ResultsTwo clinical trials involving 24 patients were included in this review. High immunogenicity was observed in both studies. The GAPVAC-101 trial reported 50% APVAC1-induced and 84.7% APVAC2-induced immunogenicity with CD8+ and CD4+ T cell responses in 92% (12/13) and 80% (8/10) immune responders, respectively. Two out of five patients showed CD4+ and CD8+ T cell responses in the study by Keskin et al. Dexamethasone use had limited immunogenicity in a trial by Keskin et al (6/8). No serious treatment-related adverse events were reported.ConclusionActively personalized vaccines aimed at unmutated peptides and neoantigens for patients with GBM are safe and highly immunogenic, particularly when administered in combination. Larger studies are warranted to investigate the role.
| S-EPMC8427683 | biostudies-literature
Project description:Glioblastoma is a refractory malignancy with limited treatment options at tumor recurrence. Only a small proportion of patients survive 2 years or longer with the current standard of care. Gene expression profiling can segregate newly diagnosed patients into groups with different prognoses, and these biomarkers are being incorporated into a new generation of personalized clinical trials. Using the experience from recently completed large scale, multi-faceted, randomized glioblastoma clinical trials, a new clinical trial paradigm is being established to move promising therapies forward into the newly diagnosed treatment setting. Upcoming trials using the immune check-point inhibitors are an example of this changing paradigm and these and other immunotherapies have potential as promising new treatment modalities for newly diagnosed GB patients.
| S-EPMC4673777 | biostudies-literature