TB-08MECHANISMS OF IMMUNE RESISTANCE IN PEDIATRIC POSTERIOR FOSSA TUMORS
Bibliographic record
Abstract
Posterior fossa tumors (PFT) such as medulloblastoma (MB) and atypical teratoid rhabdoid tumor (ATRT) are aggressive and malignant pediatric brain tumors. Tumor recurrence is common with no available cure. The current standard-of-care can cause significant morbidities including a sharply elevated risk for secondary malignancies, ototoxicity and neurophysiological sequelae. Here, we offer a new therapeutic approach for children with recurrent/refractory PFT, which harnesses the killing capacity of natural killer (NK) cells. This is predicated on our ability to deliver ex vivo expanded and activated clinical grade NK cells to the tumor microenvironment through an ommaya reservoir. In pre-clinical studies we observed that many MBs and ATRT were susceptible to NK cells in vitro and in vivo. These observations provided support for a first in humans Phase I trial (NCT02271711) to examine the safety and feasibility of infusing NK cells into the fourth ventricle of patients with recurrent/refractory PFTs. Our in vitro studies also identified resistance to NK-mediated lysis in a subset of MBs and ATRTs. This resistance was caused by the epigenetic upregulation of the growth and differentiation factor-1 (GDF-1), a member of the TGF-beta family, in ATRTs and the elevated expression of the programmed death-ligand 1 (PD-L1) in MBs. Their genetic and pharmacological manipulation countered tumor cell resistance to cytolysis by NK cells. Mis-regulation of these molecules was also observed in patient samples, setting the stage for their development as biomarkers to predict tumor response, and providing justification for subsequent clinical trials combining NK cells with epigenetic modifiers.
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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 | 0.000 | 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".