539. Clinical LV Design Incorporating Human-Derived Cell-Fate Control (Suicide) Elements
Bibliographic record
Abstract
We have previously reported on cell-fate control or ‘suicide’ transgenes based on the human enzymes deoxyCytidine Kinase (dCK) and Thymidylate Kinase (tmpK). These cell-fate control systems are based on modified human kinases, which convert exogenous non-toxic pro-drugs into toxic products. Modified dCK activates bromovinyldeoxyuridine (BVdU), l-deoxythymidine (LdT), l-deoxyuridine (LdU), etc., to become cytotoxic compounds that induce apoptosis. Modified tmpK specifically acts on metabolites of azidothymidine (AZT). It converts AZT-MP to AZT-DP. Subsequent conversion to AZT-TP results in inducible-programmed cell death of tmpK-transduced cells. Recently we have fused these ‘suicide’ transgenes to a cytoplasmic tail-truncated human LNGFR (CD271), a cell surface marker, enforcing a one-to-one correlation between components. Both the trLNGFRdCK and trLNGFRtmpK constructs follow an IRES element in bicistronic lentivectors (LVs) ensuring transfer of the therapeutic construct and the cell-fate control element into the same target cells. This system offers a robust method to eradicate transduced cells at the end of treatment or upon observation of adverse events. It also provides a facile method for vector tracking, and facilitates the evaluation of vector transduction efficiency and selection of expanded transduced cells ex vivo. Currently, we are engineering these cell-fate control elements into 3 independent LVs for clinical application: 1) in an IL-12-based construct to generate anti-tumor vaccines in AML, 2) to engineer overexpression of a lysosomal hydrolase to treat Fabry disease, and 3) to mitigate the graft-versus-host disease response resulting from adoptive T cell transfers. Pre-clinical data suggests significant expression of IL-12 in ex vivo transduced patient AML blasts and near complete AZT-responsive cell death. Our LV designed for treatment of Fabry disease restores stable alpha-galactosidase A activity in ex vivo-transduced CD34+ HSCs and provides a mechanism for their death upon AZT addition if needed. The trLNGFRtmpK construct will provide a marker for ex vivo expansion of T cells carrying the cell-fate control cassette and allow for selective ablation of those cells if graft-versus-host disease occurs. Indeed, we have observed significant transduction frequencies and inducible death of transduced human T cells upon AZT addition. The trLNGFRdCK and trLNGFRtmpK constructs are novel human-derived cell-fate control (‘suicide’) elements for use in clinical vector design.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.002 | 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 | 0.001 | 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".