■建立的HER2+癌症小鼠模型是基于啮齿动物Neu/Erbb2同源物的过表达,与人类HER2(huHER2)靶向治疗不相容。此外,免疫缺陷异种移植或转基因模型的使用排除了对天然抗肿瘤免疫应答的评估.这些障碍对我们理解huHER2靶向免疫疗法背后的免疫机制是一个挑战。
■为了评估我们的huHER2靶向组合策略的免疫影响,我们建立了huHER2+乳腺癌的同基因小鼠模型,使用截短形式的huHER2,HER2。在验证此模型后,接下来,我们采用我们的免疫治疗策略治疗荷瘤患者:溶瘤性水泡性口炎病毒(VSVΔ51)和临床批准的抗体-药物偶联物靶向huHER2曲妥珠单抗emtansine(T-DM1).我们通过肿瘤控制来评估疗效,生存,和免疫分析。
当在鼠乳腺癌4T1.2细胞中表达时,产生的截短的HER2T构建体在野生型BALB/c小鼠中是非免疫原性的。与对照组相比,用VSVΔ51+T-DM1治疗4T1.2-HER2T肿瘤产生了强大的疗效,和广泛的免疫记忆。抗肿瘤免疫的询问显示CD4+T细胞浸润肿瘤,和B的激活,NK,和树突状细胞反应,以及肿瘤反应性血清IgG。
4T1.2-HER2T模型用于评估我们的复杂药物病毒治疗策略后的抗肿瘤免疫应答。这些数据证明了同基因HER2T模型在体内免疫活性设置中用于评估huHER2靶向治疗的实用性。我们进一步证明,HER2T可以在多个其他同系肿瘤模型中实施,包括但不限于结直肠和卵巢模型。这些数据还表明,HER2T平台可用于评估一系列表面HER2T靶向方法。比如CAR-T,T细胞衔接者,抗体,甚至重新定位溶瘤病毒。
Established mouse models of HER2+ cancer are based on the over-expression of rodent Neu/Erbb2 homologues, which are incompatible with human HER2 (huHER2) targeted therapeutics. Additionally, the use of immune-deficient xenograft or transgenic models precludes assessment of native anti-tumour immune responses. These hurdles have been a challenge for our understanding of the immune mechanisms behind huHER2-targeting immunotherapies.
To assess the immune impacts of our huHER2-targeted combination strategy, we generated a syngeneic mouse model of huHER2+ breast cancer, using a truncated form of huHER2, HER2T. Following validation of this model, we next treated tumour-bearing with our immunotherapy strategy: oncolytic vesicular stomatitis virus (
VSVΔ51) with clinically approved antibody-drug conjugate targeting huHER2, trastuzumab emtansine (T-DM1). We assessed efficacy through tumour control, survival, and immune analyses.
The generated truncated HER2T construct was non-immunogenic in wildtype BALB/c mice upon expression in murine mammary carcinoma 4T1.2 cells. Treatment of 4T1.2-HER2T tumours with
VSVΔ51+T-DM1 yielded robust curative efficacy compared to controls, and broad immunologic memory. Interrogation of anti-tumour immunity revealed tumour infiltration by CD4+ T cells, and activation of B, NK, and dendritic cell responses, as well as tumour-reactive serum IgG.
The 4T1.2-HER2T model was used to evaluate the anti-tumour immune responses following our complex pharmacoviral treatment strategy. These data demonstrate utility of the syngeneic HER2T model for assessment of huHER2-targeted therapies in an immune-competent in vivo setting. We further demonstrated that HER2T can be implemented in multiple other syngeneic tumour models, including but not limited to colorectal and ovarian models. These data also suggest that the HER2T platform may be used to assess a range of surface-HER2T targeting approaches, such as CAR-T, T-cell engagers, antibodies, or even retargeted oncolytic viruses.