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 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 | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 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 ».