IMMU-07. COMBINED PD1 AND LAG3 INHIBITION IN PRECLINICAL MODELS AND PATIENTS WITH DNA REPLICATION REPAIR DEFICIENT GLIOBLASTOMA (RRD-GBM): AN IRRDC STUDY
Bibliographic record
Abstract
Abstract BACKGROUND RRD-GBM harbour high tumor mutation burden (TMB) and respond to anti-PD1 immune checkpoint inhibition (ICI). However, the majority ultimately progress, highlighting the need for combinatorial therapies for sustained immune-surveillance. METHODS We performed transcriptomic analyses of human RRD-GBM specimens for immune checkpoint expression, and accordingly, tested combined ICI in immunocompetent murine models. Based on these preclinical data, we treated refractory patients using a combination of anti-PD1 and anti-LAG3 through single-patient trials/ compassionate access. Complimentary immuno-genomic biomarker analyses including circulating tumor DNA (ctDNA) were performed to study mechanisms and track responses. RESULTS Human RRD-GBM (n=80) demonstrated high LAG3 expression, providing a strong rationale for targeting. We tested combined anti-PD1 and anti-LAG3 inhibition in three immunocompetent RRD-GBM murine models. In the anti-PD1-responsive (Nestin-Cre-MSH2LoxP/LoxP-POLES459F/+) model, combined inhibition resulted in universal tumor response and survival. In the anti-PD1 resistant models (Mlh1-/-/Nestin-Cre+/Trp53LoxP/LoxP and therapy-induced hypermutant ENU/Trp53-/- gliomas), the combination improved survival despite a lack of response to anti-PD1 monotherapy. Biologically, high LAG3 expression and exhaustion was observed in CD8 T-cells after treatment with anti-PD1, which was subsequently ablated by the addition of anti-LAG3. Serially transplanted mice showed response and improved survival to the combination, suggesting that resistance to anti-PD1 could be abrogated by the combination. Four patients with RRD-GBM who had failed anti-PD1 treatment were treated using the combination, resulting in objective radiological responses and prolonged ongoing survival in patients with RRD-GBM and high LAG3 expression. Tolerability was better than a previous study of combined CTLA4 and PD1 inhibition for similar patients. Correlation with paired immuno-genomic tumor analyses, flow-cytometry, T-cell receptor clonotype and CSF ctDNA are ongoing prospectively. CONCLUSION LAG3 is an effective target in refractory RRD-GBM. Combined inhibition with anti-PD1 inhibition demonstrated radiological response, prolonged survival and manageable toxicities in patients, and will be tested in future clinical trials.
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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".