mRNA-4157 (V940) is an individualized neoantigen therapy (INT) targeting up to 34 patient-specific tumor neoantigens to induce T cell responses and potentiate anti-tumor activity. We report mechanistic insights into the immunogenicity of mRNA-4157 via characterization of T cell responses to neoantigens from the first-in-human phase 1, KEYNOTE-603 study (NCT03313778) in patients with resected non-small cell lung cancer (Part A: 1mg mRNA-4157, n = 4) or resected cutaneous melanoma (Part D: 1mg mRNA-4157 + 200mg pembrolizumab, n = 12). Safety, tolerability, and immunogenicity were assessed. All patients experienced ≥1 treatment-emergent adverse event (AE); there were no grade 4/5 AEs or dose-limiting toxicities. mRNA-4157 alone induced consistent de novo, and strengthened pre-existing, T cell responses to targeted neoantigens. Following combination therapy, sustained mRNA-4157-induced neoantigen-specific T cell responses and expansion of cytotoxic CD8 and CD4 T cells were observed. These findings show the potential of a novel mRNA INT approach in oncology.

中文翻译：

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在 1 期 KEYNOTE-603 研究中，T 细胞对个体化新抗原疗法 mRNA-4157 （V940） 单独或与 Pembrolizumab 联合使用的反应


mRNA-4157 （V940） 是一种个体化新抗原疗法 （INT），靶向多达 34 种患者特异性肿瘤新抗原，以诱导 T 细胞反应并增强抗肿瘤活性。我们通过表征 T 细胞对新抗原的反应，从首次人体 1 期，KEYNOTE-603 研究 （NCT03313778） 中对切除的非小细胞肺癌患者（A 部分：1mg mRNA-4157，n = 4）或切除的皮肤黑色素瘤患者（D 部分：1mg mRNA-4157 + 200mg pembrolizumab，n = 12）中对 mRNA-4157 免疫原性的机制见解。评估安全性、耐受性和免疫原性。所有患者均出现 ≥1 治疗中出现的不良事件 （AE）;没有 4/5 级 AE 或剂量限制性毒性。单独的 mRNA-4157 诱导一致的从头 T 细胞反应，并加强了先前存在的 T 细胞对靶向新抗原的反应。联合治疗后，观察到持续 mRNA-4157 诱导的新抗原特异性 T 细胞反应和细胞毒性 CD8 和 CD4 T 细胞的扩增。这些发现显示了新型 mRNA INT 方法在肿瘤学中的潜力。