Lucie Stengs
A5001161042- Cancer Immunotherapy and Biomarkers
- Glioma Diagnosis and Treatment
- Genetic factors in colorectal cancer
- Childhood Cancer Survivors' Quality of Life
- Cancer Genomics and Diagnostics
- Cancer, Stress, Anesthesia, and Immune Response
- Immune cells in cancer
- Health Systems, Economic Evaluations, Quality of Life
- Acute Lymphoblastic Leukemia research
- DNA Repair Mechanisms
- Brain Metastases and Treatment
- Lung Cancer Treatments and Mutations
- Pancreatic and Hepatic Oncology Research
- Colorectal Cancer Treatments and Studies
- Neuroblastoma Research and Treatments
- RNA modifications and cancer
- Drug Transport and Resistance Mechanisms
- Immunotherapy and Immune Responses
- Radiomics and Machine Learning in Medical Imaging
- Circular RNAs in diseases
- Multiple and Secondary Primary Cancers
- RNA and protein synthesis mechanisms
- VLSI and Analog Circuit Testing
- Genomics and Rare Diseases
- Radiopharmaceutical Chemistry and Applications
Hospital for Sick Children
2020-2024
SickKids Foundation
2020-2024
Occupational Cancer Research Centre
2024
University of Toronto
2023
Great Ormond Street Hospital
2023
University College London
2023
Checkpoint inhibitors have limited efficacy for children with unselected solid and brain tumors. We report the first prospective pediatric trial (NCT02992964) using nivolumab exclusively refractory nonhematologic cancers harboring tumor mutation burden (TMB) ≥5 mutations/megabase (mut/Mb) and/or mismatch repair deficiency (MMRD).
Abstract Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI monotherapy unknown. We performed an international study on 75 patients treated with anti–PD-1; 20 are progression free (median follow-up, 3.7 years). After second progression/recurrence (n = 55), continuing ICI-based salvage prolonged survival to 11.6 months 38; P < 0.001), particularly...
Abstract With the success of immunotherapy in cancer, understanding tumor immune microenvironment (TIME) has become increasingly important; however pediatric brain tumors this remains poorly characterized. Accordingly, we developed a clinical immune-oncology gene expression assay and used it to profile diverse range 1382 samples with detailed molecular annotation. In low-grade gliomas identify distinct patterns activation prognostic significance BRAF V600E-mutant tumors. high-grade gliomas,...
PURPOSE Diagnosis of Mismatch Repair Deficiency (MMRD) is crucial for tumor management and early detection in patients with the cancer predisposition syndrome constitutional mismatch repair deficiency (CMMRD). Current diagnostic tools are cumbersome inconsistent both childhood cancers determining germline MMRD. PATIENTS AND METHODS We developed analyzed a functional Low-pass Genomic Instability Characterization (LOGIC) assay to detect The performance LOGIC was compared that current...
Constitutional mismatch repair deficiency (CMMRD) is a rare syndrome characterized by an increased incidence of cancer. It caused biallelic germline mutations in one the four genes (MMR) genes: MLH1, MSH2, MSH6, or PMS2. Accurate diagnosis accompanied proper molecular genetic examination plays crucial role cancer management and also has implications for other family members. In this report, we share impact challenges during clinical two brothers with CMMRD from non-consanguineous harbouring...
Abstract We report a case of Mismatch Repair Deficiency (MMRD) caused by germline homozygous EPCAM deletion leading to tissue-specific loss MSH2. Through the use patient-derived cells and organoid technologies, we performed stepwise in vitro differentiation colonic brain organoids from reprogrammed del iPSC derived patient fibroblasts. Differentiation epithelial-colonic exhibited continuous increased expression hypermethylation MSH2 promoter. This was associated with expression, mutational...
Abstract Mutations accumulate in the genome of every cell body throughout life, causing cancer and other genetic diseases 1-4 . Almost all these mosaic mutations begin as nucleotide mismatches or damage only one two strands DNA prior to becoming double-strand if unrepaired misrepaired 5 However, current sequencing technologies cannot resolve initial single-strand events. Here, we developed a single-molecule, long-read method that achieves single-molecule fidelity for single-base...
Abstract Background Constitutional mismatch repair deficiency (CMMRD) is a rare and extraordinarily penetrant childhood-onset cancer predisposition syndrome. Genetic diagnosis often hampered by the identification of (MMR) variants unknown significance difficulties in PMS2 analysis, most frequently mutated gene CMMRD. We present validation robust functional tool for CMMRD characterization microsatellite instability (MSI) patterns blood tumors. Methods The highly sensitive assessment MSI...
Abstract BACKGROUND IDH-mutant gliomas comprise <10% of HGG in children. RRD-HGG 5-10% childhood HGG, demonstrate high mutation burden (TMB) and respond to immune-checkpoint inhibition (ICI). The impact RRD with gliomas, effective therapeutic options for these patients are not well-established. METHODS Clinical multi-omic analyses were performed on IDHmut-RRD-HGG registered the IRRDC glioma taskforce. Tumor development genomic data studied from a novel immunocompetent mouse model....
Abstract BACKGROUND RRD-GBM harbour high tumor mutation burden (TMB) and respond to anti-PD1 immune checkpoint inhibition (ICI). However, the majority ultimately progress, highlighting need for combinatorial therapies sustained immune-surveillance. METHODS We performed transcriptomic analyses of human specimens expression, accordingly, tested combined ICI in immunocompetent murine models. Based on these preclinical data, we treated refractory patients using a combination anti-LAG3 through...
Abstract BACKGROUND Replication-repair deficiency (RRD) stemming from mismatch repair and polymerase-proofreading gene defects (MMRD/PPD) lead to hypermutant childhood cancers, most frequently brain tumors. While medulloblastoma is reported, the clinical, genomic immune landscape remains unknown. METHODS We analysed genome, methylome, transcriptome (bulk, single-nuclei) immune-microenvironment of largest cohort RRD-medulloblastoma patients enrolled by International RRD Consortium, correlated...
Abstract Mismatch repair deficiency (MMRD) is a pan-cancer mechanism resulting in universal hypermutation. MMRD-gliomas are resistant to chemoradiation but respond immunotherapy. MMRD can occur somatically or be inherited as part of Lynch Syndrome (LS) Constitutional Repair Deficiency (CMMRD). However, the prevalence gliomas children, adolescents, and young adults (CAYA), impact germline inheritance unknown. We utilized functional genomic tools on population-based validation cohorts from 3...
Abstract BACKGROUND: High-grade gliomas (HGG) with replication-repair deficiency (RRD) harbour high mutation burden (TMB) and are rapidly fatal following chemo-radiation approaches. Although hypermutation results in objective responses prolonged survival >30% of patients undergoing PD1-blockade, salvage failure PD1-inhibition remains a challenge. METHODS: We performed real-world study Ipilimumab (anti-CTLA4) combination Nivolumab/Pembrolizumab for failing single-agent PD1-inhibition....
<div>AbstractPurpose:<p>Checkpoint inhibitors have limited efficacy for children with unselected solid and brain tumors. We report the first prospective pediatric trial (NCT02992964) using nivolumab exclusively refractory nonhematologic cancers harboring tumor mutation burden (TMB) ≥5 mutations/megabase (mut/Mb) and/or mismatch repair deficiency (MMRD).</p>Patients Methods:<p>Twenty patients were screened, 10 ultimately included in response cohort of whom nine had TMB...
<div>Abstract<p>Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI monotherapy unknown. We performed an international study on 75 patients treated with anti–PD-1; 20 are progression free (median follow-up, 3.7 years). After second progression/recurrence (<i>n</i> = 55), continuing ICI-based salvage prolonged survival to 11.6...
<div>Abstract<p>Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI monotherapy unknown. We performed an international study on 75 patients treated with anti–PD-1; 20 are progression free (median follow-up, 3.7 years). After second progression/recurrence (<i>n</i> = 55), continuing ICI-based salvage prolonged survival to 11.6...
<p>Patients with RRD-HGG treated ICI (<i>n</i> = 75). <b>A,</b> Cohort characteristics. <b>B,</b> Flow of patients RRD-HGGs ICIs and salvage regimens. MEK-i, MEK inhibitor. <b>C,</b> Progression-free (PFS1) overall survival (OS1) on anti–PD-1/PDL1 monotherapy. <b>D,</b> Overall (OS2) for 55 progressing monotherapy stratified by continued 38) or no 17). PPAP, polymerase proofreading associated polyposis syndrome; CMMRD,...
<p>Patients treated with nivolumab and trametinib (<i>n</i> = 5). <b>A,</b> Objective responses in bifocal glioblastoma progressing on nivolumab. <b>B</b>, Swimmer's plot summarizing events each patient. <b>C</b>, The patient at primary distant sites had complete response being simultaneously radiation addition of to T-cell receptor (TCR) clonotype analysis shows an initial increase TCRB after starting nivolumab, invigoration salvage...
<p>Supplementary Figures S1 to S5, with each figure followed by its corresponding legend in the next page</p>
<p>Patients receiving dual-checkpoint inhibition with ipilimumab and anti–PD-1 after failing ICI monotherapy (<i>n</i> = 24). <b>A,</b> Swimmer's plot for each patient, showing the best documented radiologic response at any time during treatment. Inset, representative image to inhibition. <b>B,</b> Progression-free (PFS2) overall survival (OS2). <b>C,</b> Normalized CTLA4 expression counts generated using NanoString platform (Methods)...
<p>Patients with RRD-HGG treated ICI (<i>n</i> = 75). <b>A,</b> Cohort characteristics. <b>B,</b> Flow of patients RRD-HGGs ICIs and salvage regimens. MEK-i, MEK inhibitor. <b>C,</b> Progression-free (PFS1) overall survival (OS1) on anti–PD-1/PDL1 monotherapy. <b>D,</b> Overall (OS2) for 55 progressing monotherapy stratified by continued 38) or no 17). PPAP, polymerase proofreading associated polyposis syndrome; CMMRD,...
<p>Impact of radiotherapy. <b>A,</b> Patient progressing on nivolumab received reirradiation, following which further progression prompted the addition ipilimumab. This was followed by radiologic flare, and continued treatment with supportive care led to delayed response. <b>B,</b> Impact reirradiation survival. <b>C,</b> additional (RT) in patients who <b>D,</b> Relative contribution radiation-induced indel signature (ID8) RRD-HGG...
<p>Baseline characteristics of patients with RRD high-grade gliomas treated immune-checkpoint inhibition (ICI) (n=75)</p>