Abstract A029: SQ3370: CAPAC platform enables tumor-localized therapy and minimizes systemic toxicities
Notice bibliographique
Résumé
Abstract Conventional chemotherapies lack specificity for tumor tissue, have a low therapeutic index, and induce systemic toxicities including cardiomyopathy. SQ3370 utilizes the Click Activated Protodrugs Against Cancer (CAPAC) platform to localize doxorubicin (Dox) to tumor tissue while minimizing systemic exposure. SQ3370 consists of an intratumoral injection of a biopolymer followed by 5 daily intravenous doses of an attenuated protodrug of Dox. The tumor-localized activation of Dox is enabled by mutually reactive click chemistry groups on the biopolymer and protodrug, and is therefore agnostic to tumor characteristics that can vary from patient to patient. This allows the CAPAC platform to be readily applicable to diverse tumor types, including heterogeneous sarcoma subtypes. The lead candidate, SQ3370 is currently being evaluated in a Phase I study in patients with advanced solid tumors (NCT04106492). In preclinical studies, SQ3370 treatment showed reduced toxicity, enabling doses of 19.1-fold and 8.9-fold the maximum tolerated dose of conventional Dox in mice and dogs, respectively. Further, there was no evidence of cardiotoxicity in dogs at this dose. In syngeneic dual-tumor mouse models of MCA205 fibrosarcoma, MC38 colon carcinoma, and B16-F10 melanoma, only one tumor was injected with the biopolymer. Following 5 daily intravenous doses of the protodrug, dose-dependent antitumor responses were seen in the injected and non-injected lesions across all syngeneic models. Furthermore, T-cell infiltration was observed in both lesions of the MC38 dual-tumor model, suggesting activation of an antitumor immune response by SQ3370. The combination of SQ3370 with an immune adjuvant (TLR9 agonist) further prolonged overall survival, improved the antitumor response, and increased the number of complete responses compared to the monotherapy, likely by enhancing the immune activation effects of SQ3370. Conventional Dox can induce cardiomyopathy at incidences of 1-20% for cumulative doses from 300-500 mg/m2 in humans. In the Phase I trial, SQ3370 was well tolerated in patients receiving more than 1000 mg/m2 Dox in cumulative doses. Treated tumors included sarcoma (73%), breast cancer (7.7%), gyne (7.7%), and others (11.5%). Dose escalation is ongoing. Most frequent adverse events (AEs), included nausea, fatigue, and anemia. Ejection fraction (LVEF), indicative of cardiac function, remained normal during the study period. No AEs that led to discontinuation or death were related to SQ3370 by investigator assessment.In summary, SQ3370 facilitates localization of Dox at the tumor with minimal systemic toxicity and demonstrates the first proof of concept of the click chemistry-based CAPAC platform. The CAPAC Platform represents a new therapeutic modality to treat solid tumors by using a drug with known efficacy, such as Dox, and expanding its pharmacological capabilities. Citation Format: Jose M. Mejia Oneto, Sangeetha Srinivasan, Jesse M. McFarland, Matthew Tso, Masa Aleckovic. SQ3370: CAPAC platform enables tumor-localized therapy and minimizes systemic toxicities [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A029.
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) | 0,000 | 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 | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,006 | 0,002 |
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 ».