Ena-DATASET-JHU-UAD-14-09-2018-18:13:52:593-711 - samples
Ontology highlight
ABSTRACT:
PROVIDER: EGAD00001004336 | EGA |
REPOSITORIES: EGA
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Project description:In this manuscript, the authors had hypothesized a multi-dimensional approach modeling of both tumor and immune-related molecular mechanisms would better predict immune checkpoint blockade (ICB) response than simpler mutation-focused biomarkers, such as tumor mutational burden (TMB). The authors showed that the predictive power increases with deeper modeling of neoantigens and immune-related resistance mechanisms of ICB. The neoantigen burden score (NBS) and composite neoantigen presentation score (NEOPS) mentioned in the transcript was fully reproduced. Internally they used XGBoost algorithm to generate the results and the same is provided as dataset file. That is, the dataset provided here demonstrates that their integrative approach outperformed single-analyte biomarkers such as those found in cohort of patients with late-stage melanoma. This model is now addresses the issues in reproducing itself which was caused by version changes and deprecation of some R packages. It uses checkpoint package, which acts as a time machine for CRAN packages thereby promoting FAIReR sharing of ML models.
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Project description:Cancer somatic mutations can generate neoantigens that distinguish malignant from normal cells. Such neoantigens have been implicated in response to immunotherapies including immune checkpoint blockade, yet their identification and validation remains challenging. Here we discover neoantigens in human mantle cell lymphomas using an integrated strategy for genomic and proteomic tumor antigen discovery that interrogates peptides presented within the tumor major histocompatibility complex (MHC) class I and class II molecules. We applied this approach to systematically identify neoantigen peptides in diagnostic tumor specimens from 17 patients. Remarkably, the 52 discovered neoantigenic peptides were invariably derived from the lymphoma immunoglobulin (Ig) heavy or light chain variable regions. Although we could identify MHC presentation of private germline polymorphic alleles, no mutated peptides were recovered from non-Ig somatically mutated genes. The immunoglobulin variable region somatic mutations were almost exclusively presented by MHC-II. We found T-cells specific for an immunoglobulin-derived neoantigen in the blood of a patient using MHC-II tetramers, and these T-cell clones expanded in frequency following tumor vaccination. These results demonstrate that an integrative approach combining MHC isolation, peptide identification and exome sequencing is an effective platform to uncover tumor neoantigens. Application of this strategy to human lymphoma implicates immunoglobulin neoantigens as targets for lymphoma immunotherapy.
2017-03-27 | PXD004746 | Pride
Project description:Cancer somatic mutations can generate neoantigens that distinguish malignant from normal cells. Such neoantigens have been implicated in response to immunotherapies including immune checkpoint blockade, yet their identification and validation remains challenging. Here we discover neoantigens in human mantle cell lymphomas using an integrated strategy for genomic and proteomic tumor antigen discovery that interrogates peptides presented within the tumor major histocompatibility complex (MHC) class I and class II molecules. We applied this approach to systematically identify neoantigen peptides in diagnostic tumor specimens from 17 patients and several cell lines. Remarkably, the discovered neoantigenic peptides were invariably derived from the lymphoma immunoglobulin (Ig) heavy or light chain variable regions. Although we could identify MHC presentation of private germline polymorphic alleles, no mutated peptides were recovered from non-Ig somatically mutated genes. The immunoglobulin variable region somatic mutations were almost exclusively presented by MHC-II. We found T-cells specific for an immunoglobulin-derived neoantigen in the blood of a patient using MHC-II tetramers, and these T-cell clones expanded in frequency following tumor vaccination. These results demonstrate that an integrative approach combining MHC isolation, peptide identification and exome sequencing is an effective platform to uncover tumor neoantigens. Application of this strategy to human lymphoma implicates immunoglobulin neoantigens as targets for lymphoma immunotherapy.
2017-03-27 | PXD005704 | Pride
Project description:The dataset for Multimodal Genomic Features Predict Outcome of Immune Checkpoint Blockade in Non-small Cell Lung Cancer includes 106 bam files from whole exome next-generation sequencing on the Illumina HiSeq2500. The samples analyzed include matched tumor/normal samples from non-small cell lung cancer patients treated with immunotherapy.
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Project description:Tumor cell-containing Regions of Interest from 17 patients with melanoma after progression to Immune Checkpoint Blockade were profiled at the transcriptomic level.
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Project description:Immune checkpoint blockade has limited efficacy in microsatellite stable (MSS) colorectal (CRC) and pancreatic (PDAC) cancer. Preclinical models have demonstrated the use of radiation to activate the innate immune response and stimulate responsiveness to immune checkpoint blockade. Here, we describe a Phase 2 trial of radiation therapy combined with combined anti-CTLA4 (ipilimumab) and anti-PD1 (nivolumab) antibodies in MSS CRC and PDAC. In the per protocol analysis disease control rate was 37% (10/27) in CRC and 29% (5/17) in PDAC with an overall response rate of 15% (4/27) and 18% (3/17), respectively. Whole exome and RNA sequencing of biopsies from 17 patients revealed low tumor mutational burden in all tumors, but a notable upregulation of interferon stimulated genes with concordant high expression of multiple repeat RNA transcripts in responders. Altogether, this study provides foundational human proof of concept of radiation with combination immune checkpoint blockade therapy in otherwise immunotherapy resistant cancers.
2021-07-06 | GSE179351 | GEO
Project description:Neoantigen vaccines aiming to induce and amplify tumor-specific T cell responses have received promising anti-tumor effect in early clinical trials. However, the underlying mechanism regarding response or resistance to this treatment remains unclear. Here, we observed that neoantigen vaccine-generated T cells could synergize with immune checkpoint blockade (ICB) for effective tumor control. Specifically, we performed single-cell sequencing on over 100,000 T cells and uncovered that combined therapy induced a novel antigen-specific CD8 T cell population with active chemokine signaling (Cxcr3+/Ccl5+), lower co-inhibitory receptor expression (Lag3-/Havcr2-) and higher cytotoxicity (Fasl+/Gzma+). Furthermore, the generation of antigen specific T cells in the drain lymph node is required for combination treatment mediated therapeutic effect. Signature genes of this unique population is associated with T cell clonal frequency and better survival in human. Our study comprehensively profiled the dynamics of tumor infiltrated T cells during neoantigen vaccine and ICB treatments, and high-dimensionally identified neoantigen-reactive T cell signatures for future development of better therapeutic strategies.
2022-01-10 | GSE178881 | GEO
Project description:The purpose of this study is to evaluate the dose, safety, immunogenicity and early clinical activity of GRT-C903 and GRT-R904, a neoantigen-based therapeutic cancer vaccine, in combination with immune checkpoint blockade, in patients with advanced or metastatic non-small cell lung cancer, microsatellite stable colorectal cancer, pancreatic cancer, and shared neoantigen-positive tumors. Based on the Phase 1 data, an updated vaccine candidate (SLATE-KRAS or version 2) was developed that removed 16 of the 20 mutations included in the original vaccine (version 1) and solely targets KRAS mutations.
| 2305807 | ecrin-mdr-crc
Project description:<p>Immune checkpoint inhibitors are effective cancer treatments, but molecular determinants of clinical benefit are unknown. Ipilimumab and tremelimumab are antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4). Anti-CTLA-4 treatment prolongs overall survival in patients with melanoma. CTLA-4 blockade activates T cells and enables them to destroy tumor cells.</p> <p>We obtained tumor tissue from patients with melanoma who were treated with ipilimumab or tremelimumab. Whole-exome sequencing was performed on tumors and matched blood samples. Somatic mutations and candidate neoantigens generated from these mutations were characterized. Neoantigen peptides were tested for the ability to activate lymphocytes from ipilimumab-treated patients.</p> <p>Malignant melanoma exomes from 64 patients treated with CTLA-4 blockade were characterized with the use of massively parallel sequencing. A discovery set consisted of 11 patients who derived a long-term clinical benefit and 14 patients who derived a minimal benefit or no benefit. Mutational load was associated with the degree of clinical benefit (P = 0.01) but alone was not sufficient to predict benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA typing, we identified candidate tumor neoantigens for each patient. We elucidated a neo-antigen landscape that is specifically present in tumors with a strong response to CTLA-4 blockade. We validated this signature in a second set of 39 patients with melanoma who were treated with anti-CTLA-4 antibodies. Predicted neoantigens activated T cells from the patients treated with ipilimumab.</p>
| phs001041 | dbGaP