413. Pre-Clinical Preparation and Validation of Tumor Cell-Based IL-12 Immunotherapy for Acute Myeloid Leukemia
Bibliographic record
Abstract
Interleukin(IL)-12 is a potent pro-inflammatory cytokine that stimulates a variety of effector cells involved in anti-tumor immunity. Systemic administration of IL-12 has associated toxicities, however. Various strategies are being developed to reduce such toxicities by restricting IL-12 distribution. Options here include generating fusions with tumor-targeting molecules and directing gene delivery to specific cells. First – we used lentivirus vectors (LVs) to engineer expression of murine IL-12 in tumor cells ex vivo and subsequently infused such modified cells into recipient mice. This strategy restricts IL-12 to the local tumor microenvironment thereby promoting immune activation in the context of tumor-associated antigens (TAAs). Using mouse models of both leukemia and solid tumors, we found that this cell-based approach generated effective anti-tumor protection when as little as 1% of the tumor burden expressed IL-12 as long as threshold expression levels on a per cell basis were reached. Second – our groups showed that anti-tumor mechanisms here involve CD4+ killer T cells, dendritic cells, and direct cell-cell contact with effectors. Clinical translation of this cell-based IL-12 therapy is in progress in Toronto for AML using a novel LV to modify patients’ own blast cells. Patient AML cells collected to date (n = 21) were stratified based on in vivo growth kinetics and transduced with a near-GMP-grade bicistronic LV that encodes the human IL-12 cDNA as a p40-p70 fusion, as well as a mutant thymidylate kinase (tmpK) fused to the ectodomain of LNGFR (trLNGFR) as a suicide (cell-fate control) cassette. The trLNGFR/tmpK element allows selection and also selective ablation of transduced cells by administration of AZT. Furthermore, it also allows tracking of transduced cells and quantification of transduction frequencies/transgene expression levels. With our current protocol, functional transduction efficiencies of primary patient AML blasts ranged from 20% to 70% (n=17). Transduced AML cells displayed a strong correlation between vector copy number and trLNGFR/tmpK + IL-12 levels and dose-dependent sensitivity to AZT. In vitro immortalization (IVIM) assays determined that the near-GMP LV/IL-12 vector displayed minimal genotoxic risk in transduced lin- cells; insertion site analyses carried out on expanded clones displayed poly-to oligo-clonality patterns. Pre-clinical data on toxicity and scale-up considerations are being accumulated in preparation for a Clinical Trial Application to Health Canada targeting AML. This LV/IL-12 immunotherapy platform targeting tumor cells themselves thus holds potential to be effective against a wide variety of cancers.
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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".