Correlation of immune-related adverse events with peripheral baseline immune markers and overall survival in patients with metastatic melanoma on ipilimumab and chemotherapy.
Bibliographic record
Abstract
9561 Background: Very few predictive markers have been validated for immune-related adverse events (irAE), which are the number one reason for cessation of treatment and treatment-related deaths on checkpoint inhibitors. In a phase II trial of combined ipilimumab (ipi) with carboplatin/paclitaxel (C/P) (NCT01676649), we sought to determine baseline peripheral blood markers predictive of irAEs and to correlate these adverse with subsequent survival. Methods: Thirty patients with untreated unresectable/metastatic melanoma were treated with C (AUC = 6) and P (175mg/m2) every 3 weeks x 5 and Ipi (3mg/kg) every 3 weeks x 4. irAEs were graded according to the CTCAE v5.0. Median follow-up was 60 months. Baseline blood markers was assessed by a 37 multiplex cytokine-chemokine platform (Meso Scale Discovery) and multiparameter flow cytometry. Results: Grade 2 or higher irAE occurred in 11/30 of patients (4 colitis, 2 hepatitis, 2 hypophysitis, 3 rash). Median survival was 43.8 months in patients with irAE and 14.5 months for those without irAE (p = 0.001). Pts with irAE had lower baseline circulating levels of IL-6 (3.6 vs. 19.8 pg/mL, p = 0.049), TNF alpha (7.6 vs. 11.6 pg/mL, p = 0.003), CXCL9 (83.4 vs. 116.8 pg/mL, p = 0.042) and CCL3 (52.3 vs. 76.4 pg/mL, p = 0.012), but higher baseline circulating dendritic cells (DC) (4.9 vs. 2.9 % of total PBMC, p = 0.002) and a lower level of myeloid-derived suppressor cells (MDSC) (0.8 vs. 1.7 %, p = 0.049). There was no correlation between baseline B cell circulating numbers or differentiation and irAEs. Conclusions: Although results from previous studies of ipi monotherapy vary, our small study shows a highly significant correlation between irAEs and improved long term outcome for patients treated with ipi/C/P. Our exploratory analysis also identifies putative predictive immune and cytokine-chemokine markers of irAEs, which are associated with: 1) Antigen presentation dysregulation (high DC cells) and lack of adequate auto-immune suppression (low MDSC), as also seen in classic autoimmune diseases; and 2) A low inflammatory baseline signature (low TNF, IL-6, CCL3, CXCL9) consistent with possible immune exhaustion and reduced lymphocytic homeostatic fitness. Our combined markers depict a dysregulated immune landscape favorable to the expansion of self-reactive immune cells under CTLA-4 blockade. Our results are hypothesis generating and require further evaluation in a larger group of patients, including PD-1 treated cohorts. Clinical trial information: NCT01676649.
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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) | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".