Abstract P2-09-16: CD8 T cells induced by novel alphaviral vector predict improved progression free survival in advanced HER2+ breast cancer patients

Erika J. Crosby, W. Gwin, Serena Chang, H. Maecker, Veronica Lubkov, J. Snyder, G. Broadwater, T. Hyslop, T. Osada, A. Hobeika, Z. Hartman, M. Morse, H. Lyerly
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Abstract

Background: Immune-based therapy for metastatic breast cancer has had limited success. Strategies to augment adaptive immunity include vaccines targeting genomic amplifications like Human Epidermal Growth Factor Type 2 (HER2), an established driver of malignancy. Using a novel alphaviral vector, we constructed a vaccine encoding a portion of HER2 (VRP-HER2). Methods: In preclinical studies, mice were immunized before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and anti-tumor function were assessed. We then translated this vaccine into a phase I clinical trial in which subjects with advanced HER2-overexpressing breast cancers received VRP-HER2 every 2 weeks for a total of three doses (cohort 1). In cohort 2, subjects received the same dose of VRP-HER2 along with a standard HER2 targeted therapy. Results: VRP-HER2 induced HER2-specific T cell and antibody responses while controlling tumor growth in murine models. Vaccination with VRP-HER2 was well tolerated in both patient cohorts. PFS was modest, while median OS was 50.2 months in cohort 1 and 32.7 months in cohort 2. In cohort 2, there is one partial response and two patients with continued stable disease. Vaccine induced anti-HER2 antibodies and T cells were identified. Increased perforin expression by memory CD8 T cells post vaccination significantly correlated with improved PFS. Conclusions: VRP-HER2 led to an increase in perforin expressing HER2-specific memory CD8 T cells in preclinical and clinical studies, and had profound antitumor effects in murine models. The generation of HER2-specific memory CD8 T cells was significantly correlated with increased PFS in patients. Subsequent studies will seek to enhance T cell activity by combination with anti-PD-1/PD-L1 antibodies. Citation Format: Crosby EJ, Gwin WR, Chang S, Maecker HT, Lubkov V, Snyder JC, Broadwater G, Hyslop T, Osada T, Hobeika AC, Hartman ZC, Morse MA, Lyerly HK. CD8 T cells induced by novel alphaviral vector predict improved progression free survival in advanced HER2+ breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-16.
摘要:新型α病毒载体诱导CD8 T细胞可改善晚期HER2+乳腺癌患者的无进展生存期
背景:以免疫为基础的治疗转移性乳腺癌的成功率有限。增强适应性免疫的策略包括针对基因组扩增的疫苗,如人类表皮生长因子2型(HER2),这是恶性肿瘤的既定驱动因素。利用一种新的α病毒载体,我们构建了一种编码HER2部分的疫苗(VRP-HER2)。方法:在临床前研究中,小鼠在植入hHER2+肿瘤细胞之前或之后进行免疫接种,评估her2特异性免疫反应和抗肿瘤功能。随后,我们将该疫苗转化为I期临床试验,在该试验中,晚期HER2过表达乳腺癌患者每两周接受VRP-HER2,共三次剂量(队列1)。在队列2中,受试者接受相同剂量的VRP-HER2以及标准的HER2靶向治疗。结果:VRP-HER2在小鼠模型中诱导her2特异性T细胞和抗体反应,同时控制肿瘤生长。在两组患者中,VRP-HER2疫苗接种耐受性良好。PFS适中,而队列1的中位OS为50.2个月,队列2的中位OS为32.7个月。在队列2中,有1例部分缓解,2例病情持续稳定。鉴定出疫苗诱导的抗her2抗体和T细胞。接种后记忆性CD8 T细胞穿孔蛋白表达的增加与PFS的改善显著相关。结论:在临床前和临床研究中,VRP-HER2可导致her2特异性记忆CD8 T细胞穿孔素表达增加,并在小鼠模型中具有明显的抗肿瘤作用。her2特异性记忆CD8 T细胞的产生与患者PFS的增加显著相关。后续研究将寻求通过联合抗pd -1/PD-L1抗体来增强T细胞活性。引用格式:Crosby EJ, Gwin WR, Chang S, Maecker HT, Lubkov V, Snyder JC, Broadwater G, Hyslop T, Osada T, Hobeika AC, Hartman ZC, Morse MA, Lyerly HK。新型α病毒载体诱导CD8 T细胞可预测晚期HER2+乳腺癌患者无进展生存期的改善[摘要]。2018年圣安东尼奥乳腺癌研讨会论文集;2018年12月4-8日;费城(PA): AACR;中国癌症杂志,2019;79(4增刊):2012-09-16。
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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