114P Exploring the role of FES kinase in natural killer cells to enhance immunotherapy
Bibliographic record
Abstract
Background: Cytokine release syndrome (CRS) and immune cell associated neurotoxicity syndrome (ICANS) are major toxicities associated with CD19-directed CAR Tcell therapies.These toxicities result from supraphysiologic release of inflammatory cytokines such as IL-6, IFN-, TNF-, and chemokines like MCP-1 and IP-10.While systemic corticosteroids or IL-6 receptor blockade can be used in the treatment of these toxicities, they may broadly suppress inflammatory signaling pathways placing vulnerable patient populations at risk of serious, life-threatening infections, steroid induced myopathies, or inferior outcomes.CTO1681 is a novel small molecule therapeutic designed to suppress CRS-driving cytokine production without compromising chimeric antigen receptor (CAR) T-cell function.This study evaluated the effect of CTO1681 on cytokine modulation and CAR T-cell-mediated tumor killing in vitro.Methods: Human CD19 CAR T-cells were co-cultured with Raji lymphoma cells for 24 hours at effector-to-target (E:T) ratios of 10:1, 5:1, and 1:1.CTO1681 was tested at doses ranging from 0.03 to 1 M alongside vehicle control.Inflammatory cytokines (e.g., TNF-, IL-6, IFN-) were assessed in culture supernatants using Luminex multiplexing assay.CD19 CAR T-cell mediated killing of Raji lymphoma cells was assessed using flow cytometric analysis of CD19 expressing cells.Results: CTO1681 induced a dose-dependent reduction in key CRS-associated cytokines.In the 10:1 cultures, treatment with 225 nM reduced TNF-, IL-6, and IFN- levels by 52%, 26%, and 16%, respectively, compared to untreated cells.Importantly, CTO1681 did not impair CAR T-cell-mediated cytotoxicity.Raji cell killing remained consistent across all doses of CTO1681, with killing titrated appropriately by E:T ratio: 25% at 10:1, 23% at 5:1, and 18% at 1:1.Conclusions: These findings support CTO1681 as a promising CRS-modulating agent that reduces inflammatory cytokines while preserving CAR T-cell function in vitro, warranting further development alongside CAR T-cell therapies.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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".