Abstract B025: Neutrophil depletion enhances the anti-tumor activity of CAR-T cells in an autochthonous model of non-small cell lung cancer
Notice bibliographique
Résumé
Abstract CAR-T cell therapy has produced durable clinical responses in hematological malignancies, but efficacy in more common solid tumors is limited in part by poor trafficking of CAR-T cells to tumors. Identifying strategies to improve CAR-T cell trafficking to and persistence within tumors, thus, are needed to improve efficacy against solid tumors. We previously adapted the Kras/p53 (KP) autochthonous model of non-small cell lung cancer (NSCLC) to express the CAR target ROR1 to study the mechanisms limiting the activity of ROR1 CAR-T cells. Similar to what we observed in a phase 1 trial, ROR1 CAR-T cells infiltrated KPROR1 tumors poorly and induced limited tumor control. We showed that using immunogenic chemotherapy to induce the production of T cell-recruiting chemokines significantly improved CAR-T cell infiltration into lung tumors. However, despite improved survival, many tumor nodules remained devoid of CAR-T cells, suggesting that additional mechanisms likely limit CAR-T cell access to tumors. Neutrophils have been shown to inhibit T cell infiltration and function within tumors, and high neutrophil infiltrates in NSCLC patients are associated with poor T cell infiltration and response to immunotherapy. To characterize how neutrophils may impact CAR-T cell localization, we treated KPROR1 mice with ROR1 CAR-T cells or left untreated and analyzed the co-localization of CD8+ T cells and Ly6G+ neutrophils within tumors by multiplex IHC. In untreated mice, neutrophils were primarily found around the perimeters of large tumors (>105 mm2) but were absent from small tumors (<105 mm2). Upon treatment with CAR-Ts, CD8+ T cell frequency increased across all tumors, but intratumoral T cell infiltration was significantly higher in small neutrophil-low tumors than in large neutrophil-high tumors, suggesting that neutrophil-high tumors may be less accessible to CAR-T cells. Interestingly, CAR-T treatment induced a significant increase in neutrophils, with CD8+ T cells in closer proximity to neutrophils, suggesting that CAR-Ts may promote neutrophil recruitment. We hypothesized that this increase in neutrophils might further suppress CAR-T activity. To test this, we pre-treated tumor-bearing KPROR1 mice with anti-Gr1 or a C5aR1 inhibitor, both of which have been shown to reduce neutrophil recruitment to tumors, and injected control or ROR1 CAR-T cells 2 days later. Anti-Gr1 and C5aR1 inhibitor treatments continued for 17 days after CAR-T cell injection. Whereas treatment with CAR-T cells alone had minimal effects, co-treatment with either anti-Gr-1 or C5aR1 inhibitor significantly improved survival. Our findings suggest that neutrophils may limit CAR-T infiltration and/or persistence within tumors and that neutrophil depletion can enhance the anti-tumor activity of CAR-T cells. Future work is aimed at understanding the mechanisms by which neutrophils may limit CAR-T activity. Overall, our results suggest that targeting neutrophils may be a promising strategy to overcome the major challenges in CAR-T therapy for solid tumors. Citation Format: Sergio Ortiz-Espinosa, Shivani Srivastava. Neutrophil depletion enhances the anti-tumor activity of CAR-T cells in an autochthonous model of non-small cell lung cancer [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 B025.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,001 | 0,002 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
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 tête enseignante, 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 ».