Preclinical toxicological assessment of an α-galactosylceramide-adjuvanted mRNA cancer vaccine in Wistar Han rats and domestic pigs.

IF 4.6 2区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL

Molecular Therapy-Methods & Clinical Development Pub Date : 2025-05-19 eCollection Date: 2025-06-12 DOI:10.1016/j.omtm.2025.101493

Sofie Meulewaeter, Margo De Velder, Diethard Reckelbus, Kevin Mwangi, Thomas Ehouarne, Ilke Aernout, Yanou Engelen, Fellanza Halimi, Isis Van Herteryck, Lobke De Bels, Valerie Redant, Louise De la Mane, Joline Ingels, Bo Coppens, Serge Van Calenbergh, Pieter Cornillie, Gabriële Holtappels, Benedicte Descamps, Daisy Vanrompay, Stefaan C De Smedt, Wim Van den Broeck, Bart Vandekerckhove, Mathias Devreese, Rein Verbeke, Ine Lentacker

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Abstract

Galsome-NEO is a glycolipid-adjuvanted mRNA lipid nanoparticle (LNP) cancer vaccine encoding neo-epitopes for evaluation in a phase 1 study in patients with non-small cell lung cancer. To assess the safety of Galsome-NEO, a repeated-dose toxicity study was conducted in Wistar Han rats involving three intramuscular doses of 30 μg mRNA. A dose-escalation study in piglets tested three doses of 3, 15, and 100 μg mRNA. Rats showed a pronounced pro-inflammatory response, evidenced by cytokine secretion and an acute phase reaction. Clinical findings included temporary local reactions (maximum grade 3), elevated temperatures, and weight loss. In pigs, all doses were well tolerated. Blood analysis showed elevated alkaline phosphatase and decreased thrombocytes in rats, while pigs had reduced reticulocyte counts. Histology revealed hepatocyte vacuolation in rats and immune infiltration at injection sites in both species. In rats, blood and histology alterations resolved 3 weeks post dosing, except for immune infiltration in the connective tissue at injection sites in two females. Galsomes with mRNA encoding the Chlamydia trachomatis major outer membrane protein induced T cell responses in pigs. Natural killer T cell activation was observed in both species. These findings align with the safety data for the COVID-19 mRNA vaccine, Comirnaty, and demonstrate Galsomes' potential in large animals.

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α-半乳糖神经酰胺佐剂mRNA癌疫苗对Wistar Han大鼠和家猪的临床前毒理学评价。

Galsome-NEO是一种糖脂佐剂mRNA脂质纳米颗粒（LNP）癌症疫苗，编码新表位，在非小细胞肺癌患者的1期研究中进行评估。为了评估galsomeneo的安全性，我们对Wistar Han大鼠进行了三次肌注30 μg mRNA的重复给药毒性研究。在仔猪中进行的剂量递增研究测试了3、15和100 μg mRNA的三种剂量。大鼠表现出明显的促炎反应，细胞因子分泌和急性期反应证明了这一点。临床表现包括暂时性局部反应（最高3级）、体温升高和体重减轻。在猪中，所有剂量均耐受良好。血液分析显示，大鼠的碱性磷酸酶升高，血小板减少，而猪的网织红细胞计数减少。组织学显示大鼠肝细胞空泡化，两种动物注射部位有免疫浸润。在大鼠中，除两只雌性大鼠注射部位结缔组织出现免疫浸润外，血液和组织学改变在给药后3周消失。编码沙眼衣原体主要外膜蛋白mRNA的半体诱导猪T细胞反应。在两种物种中均观察到自然杀伤T细胞活化。这些发现与COVID-19 mRNA疫苗Comirnaty的安全性数据一致，并证明了Galsomes在大型动物中的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Therapy-Methods & Clinical Development Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

9.90

自引率

4.30%

发文量

163

审稿时长

12 weeks

期刊介绍： The aim of Molecular Therapy—Methods & Clinical Development is to build upon the success of Molecular Therapy in publishing important peer-reviewed methods and procedures, as well as translational advances in the broad array of fields under the molecular therapy umbrella. Topics of particular interest within the journal''s scope include: Gene vector engineering and production, Methods for targeted genome editing and engineering, Methods and technology development for cell reprogramming and directed differentiation of pluripotent cells, Methods for gene and cell vector delivery, Development of biomaterials and nanoparticles for applications in gene and cell therapy and regenerative medicine, Analysis of gene and cell vector biodistribution and tracking, Pharmacology/toxicology studies of new and next-generation vectors, Methods for cell isolation, engineering, culture, expansion, and transplantation, Cell processing, storage, and banking for therapeutic application, Preclinical and QC/QA assay development, Translational and clinical scale-up and Good Manufacturing procedures and process development, Clinical protocol development, Computational and bioinformatic methods for analysis, modeling, or visualization of biological data, Negotiating the regulatory approval process and obtaining such approval for clinical trials.