Abstract A004: Immune response to sub-ablative radiation before surgery in pleural mesothelioma – Results from the SMARTER trial
Notice bibliographique
Résumé
Abstract Introduction. We developed a new treatment paradigm in pleural mesothelioma using a short course of sub-ablative hemithoracic radiation followed by surgery and observed encouraging results in epithelioid subtypes. We therefore performed a phase I trial to determine the safety and immunological benefit of 3 fractions of radiation before surgery. Methods. The trial, Surgery for Mesothelioma After Radiation Therapy using Extensive pleural Resection (SMARTER), was designed as a 3+3 phase I trial with incremental hemithoracic radiation dose up to 18 Gy in 3 fractions (background dose) combined with a boost of at least 39 Gy to the gross disease (boost dose). Patients with histologically confirmed stage I-III pleural mesothelioma with tumor size of at least 2 cm in diameter on CT scan were eligible for the study. Surgery was performed 7-14 days after the last fraction of radiation. CyTOF and Luminex were performed on peripheral blood at baseline pre-radiation, post-radiation at the time of surgery, and during follow-up within 3 months from surgery. Tumor was collected at the time of surgery from the sites of low dose radiation (background, T1) and high dose radiation (boost, T2) and compared to pre-radiation (baseline, T0) using single cell RNA sequencing (scRNA seq). CD8 tumor infiltrating lymphocytes (TILs) was determined by immunostaining. The results were validated in a second cohort of patients treated off trial. Results. A total of 12 patients were included in the trial with all patients safely proceeding to surgery after a background radiation dose of 0 Gy, 6 Gy, 12 Gy and 18 Gy. Total radiation boost dose ranged from 39 Gy to 54 Gy. The results were validated in a second cohort of 12 patients. Circulating IL-15, FLT-3L, and CXCL10 significantly increased at the time of surgery compared to baseline. CXCL10 continued to rise during follow-up and was associated with better survival at 1 year (86% vs 17% in the absence of CXCL10 upregulation, p=0.005). The peak of circulating IL-15 correlated with CD8 TILs in the resected tumor specimen. scRNA seq on tumor samples demonstrated that monocytes expressed IL-15 and IL-15Ra, and increased after radiation. Pseudotime trajectory analysis showed an evolution from classical to non-classical monocytes with a shift from M2-like to M1-like phenotype. This was associated with reinvigoration of cytotoxic CD8 TILs and expansion of GITR negative NK cells. CyTOF analysis on peripheral blood confirmed the upregulation of circulating monocytes followed by upregulation of CD8 effector memory T cells, which progressively decreased before tumor recurrence. Tumors with larger populations of IFN-TAM and CD8 ISG were characterized by high CXCL10 expression at baseline and a lack of CXCL10 upregulation after radiation associated with an absence of CD8 T cell reinvigoration and poor survival. Conclusions. These results demonstrate the immunogenic benefit and clinical safety of sub-ablative radiation before surgery in pleural mesothelioma. The lack of benefit was observed in tumors expressing high CXCL10 at baseline. Citation Format: Marc de Perrot, Amin Zia, Licun Wu, Giselle Boukhaled, Ramy Gadalla, Ben Wang, David Brooks, Jeffrey Man, Trevor Pugh, Prodipto Pal, Fatemeh Zaeimi, Hebe Chu, Ming-Sound Tsao, Penelope Bradbury, John Cho. Immune response to sub-ablative radiation before surgery in pleural mesothelioma – Results from the SMARTER trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A004.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,002 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».