Abstract 630: Response to nivolumab in a pediatric chordoma with overexpression of brachyury
Bibliographic record
Abstract
Abstract Chordomas are neoplasms derived from notochord cells that typically form in the spine or skull base, and affect both adults and children. Poorly differentiated chordomas, associated with particularly poor outcomes, occur predominantly in children and are characterized by expression of the transcription factor brachyury and loss of INI1/SMARCB1. The use of immune checkpoint inhibitors in pediatric cancer is of growing interest, with reported anti-tumour activity in pediatric Hodgkin lymphoma and gliomas with mismatch repair deficiency. However, responses to immune checkpoint inhibitors are infrequent and unpredictable in pediatric solid tumours, and the molecular markers that can distinguish the seemingly indiscriminate response remain to be defined. Understanding which pediatric patient populations may benefit from immune checkpoint inhibitor therapies is essential. Here we describe the molecular profiles of two pediatric poorly differentiated chordomas using whole-genome, transcriptome and whole-genome bisulfite sequencing as part of the Personalized Oncogenomics program at BC Cancer (NCT02155621) that studies the impact of embedding comprehensive genomic profiling into the clinical care of advanced cancer patients. Genomic profiling and multiplex IHC revealed a high level of CD8+ T cells in both chordoma samples, despite low mutation burden. DNA methylation-based clustering revealed similarities with SMARCB1-deficient rhabdoid tumour subtypes that are have been characterized by increased levels of immune cell infiltration. A dominant tumour-associated T cell receptor clone was identified in one patient sample, which was demonstrated to have affinity for reconstituted brachyury-MHC complexes, indicating a potential anti-tumour immune response directed against brachyury-derived antigens. As these collective observations pointed to a potential benefit of immune targeted therapy, the patient was treated with nivolumab and subsequently achieved a partial radiographic response by RANO criteria. These observations provide support for the benefit of immune checkpoint inhibitors in poorly differentiated chordomas with high levels of infiltrating CD8+ T cells. Citation Format: Laura Williamson, Craig Rive, Daniela Di Francesco, Emma Titmuss, Elizabeth Chun, Scott Brown, Katy Milne, Erin Pleasance, Anna F. Lee, Stephen Yip, David Dix, Daniel Renouf, Robert Holt, Brad H. Nelson, Martin Hirst, Steven Jones, Shahrad Rassekh, Rebecca Deyell, Janessa Laskin, Macro A. Marra. Response to nivolumab in a pediatric chordoma with overexpression of brachyury [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 630.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".