189 Baseline NKT cells as a potential predictive biomarker for treatment with an anchored IL-12 drug conjugate in patients with solid tumors
Bibliographic record
Abstract
Background IL-12 is an important cytokine for cancer immunotherapy bridging innate and adaptive immunity. IL-12 activates CD8 + T and NK cells driving effector functions that mediate anti-tumor activity. ANK-101 (tolododekin alfa) is an alum-anchored IL-12 drug conjugate designed to deliver and retain high doses of IL-12 in solid tumors. Previously, we reported a disease control rate of 60% in a first-in-human phase 1 clinical trial of superficially accessible, advanced solid tumors. Herein, we report pharmacokinetic (PK), anti-drug antibody (ADA), and pharmacodynamic parameters from peripheral blood to identify potential evidence of systemic immune activation and blood-based predictive biomarkers.Methods In a Phase 1 study ( NCT06171750), ANK-101 was administered IT every 3 weeks for up to 8 cycles using modified 3+3 dose escalation design (dose range, 6 – 250 µg/mL). Whole blood was analyzed by flow cytometry for immune profiling, IL12-ABP levels, cytokines, and ADA titers. Tumor burden was assessed every 12 weeks by CT imaging and responses recorded by RECISTv1.1. Descriptive statistics were used, with categorical variables summarized by frequency and percentage, continuous variables by mean, SD, median, and range; significance was set at P ≤ 0.05.Results PK data demonstrated that less than 1% of injected drug enters the systemic circulation. Consistent with IL-12 biology, we observed transient elevation in serum IFNγ (T max48h; median Cmax559pg/ml; range 19-6083pg/ml) post treatment with minimal changes in other measured cytokines. Only 3/15 subjects (20%) developed ADA after 3 cycles. Immunophenotyping of peripheral blood demonstrated a significant increase in the percent lymphocyte (CD45/SSC low, p=0.018, n=14), and dendritic cell (p=0.011, n=14) populations 21 days after treatment with ANK-101. A numerical increase in CD4+ central memory T cells was observed (p=0.067, n=14). ANK-101 treatment was associated with decreased Tregs (p=0.01) and a significant increase in the CD8+ T cell to Treg+ ratio (p=0.037) over the course of treatment. A significant association between higher baseline levels of peripheral blood CD3+/CD19-/CD56+ NKT cells and disease control (p=0.04: PR/stable disease; n=9 progressive disease n=5) was observed.Conclusions Alum-anchored IL-12 drug conjugate is retained locally as evidenced by limited systemic PK, ADA and cytokine changes in the serum. Systemic immune activation, however, was suggested by increased innate and adaptive immune cell populations and decreased Tregs in the peripheral blood. Higher baseline NKT cells were associated with disease control. Further studies are warranted to better define if NKT cells may serve as a predictive biomarker for IL-12 immunotherapy.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".