Initial results from a first in human trial incorporating accelerated dose titration of a novel immune stimulating oncolytic virus - VG161.
Notice bibliographique
Résumé
e14574 Background: Oncolytic virus (OV) can specifically replicate in cancer cells causing cell lysis. Together with the expression of immune stimulating payloads, OV can induce an anti-tumor immune response. The aim of this study is to assess the safety, tolerability, and PK profile of VG161, a novel HSV-1 OV armed with IL12, IL15 with its receptor α unit, and PD-L1 antagonist (Fc-fused 14 amino acid peptide), after single intra-tumoral injection (IT) in patients with advanced refractory solid tumors. Methods: This is an open label, single-arm, accelerated titration design pilot trial. Based on preclinical NOAEL, the first cohort dose level was calculated as 5×10 7 /subject, followed with 2 cohorts (1×10 8 and 2×10 8 PFU), 1-3 patients per cohort. One patient was treated in each cohort and the subsequent cohorts were initiated only after the safety observation of the current cohort was completed (21 days) with no DLT and no > 2 moderate toxicity events deemed possibly, probably, or definitely related to VG161, otherwise, it would be expanded per the 3+3 design. DNA copy number of VG161 was measured with qPCR in the tumor biopsy and blood, in urine for virus shedding, as well as swabs of injection site and mouth. Immune cytokines were measured with MSD assay (electrochemiluminescence detection) in blood. Peripheral lymphocyte subsets were analyzed with flowcytometry. Results: Three patients (1 per cohort) were treated and completed safety observation. No DLT, and 10 AEs (fever, low neutrophils and lymphocytes, etc.) were possibly, probably, or definitely related. Grade 3 fever was the only related SAE, which recovered in 3 days. Dose dependent increase of VG161 DNA copy was detected in the tumor 2-3 days after treatment (C-max: 10, 1000, and 1000000 times increase from low to high dose), in contrast, it remained undetectable in blood, oral swab, and urine. Virus DNA was detected in injection site swab for the patient at the highest dose level but not for those treated at lower dose levels. After dosing, increases of IL-12 (C-max: 2.0, 2.4, and 21 times of baseline), IL-15 (C-max: 1.6, 3.2, and 2.5 times of baseline), IFN-γ (C-max: 49, 638, and 236 times of baseline) and TNF-α (C-max: 2.3, 3.7, and 2.2 times of baseline) from low to high dose were seen. Peripheral lymphocyte subset analysis and immune profiling of injected tumor are ongoing. Interestingly, partial regression of multiple visible non-injected lesions was observed in 1 patient shortly after dosing, however no durable direct or abscopal responses were seen to date. Conclusions: Single IT injection of VG161 up to 2×10 8 PFU/subject is safe and well tolerated, with no unexpected viral spread or shedding. The post-dose increase in cytokines and the transit regression of non-injected lesions imply the activation of anti-cancer immunity induced by VG161. This holds potential for further dose optimization to assess the safety and efficacy. Clinical trial information: ACTRN12620000244909.
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 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 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 ».