Ph1 Study of T-Vec given endoscopically for advanced pancreatic cancer IN 17248 (11/21/2016)

摘要 这项孤儿药物拨款申请是为他利莫吉Laherparepvec(T-VEC)的1期临床试验，以及 经内窥镜注射溶瘤病毒治疗不能切除的胰腺癌。进阶 不幸的是，胰腺癌几乎普遍是致命的，估计令人沮丧的五年中位生存期为 6.8%是局部晚期疾病，2.8%是有远处转移的患者。我们提出了一个 研究人员发起的胰腺癌T-VEC研究，一种第一类溶瘤病毒被批准用于 黑色素瘤的治疗。目前尚无延长生存期超过几个月的治疗方法。 胰腺癌患者，免疫治疗试验的失败被归因于 胰腺癌独特的免疫抑制肿瘤微环境。溶瘤病毒，如 作为T-vec，可能通过释放危险信号和激活先天免疫来显著改变TME 小路。 这项拟议的研究已经得到食品和药物管理局的批准(IND#17248)，并提交给哥伦比亚大学 IRB，2016年11月23日(IRB#AAQ9966)。T-VEC之前曾在胰腺癌中进行过测试，结果显示效果良好 耐受性和活动度证据，在7名接受治疗的患者中，有两个轻微反应和一个稳定的疾病 测试的最高剂量比用于黑色素瘤的剂量低一个对数。这项研究被放弃了 在因财政原因达成MTD之前。我们现在建议完成这项研究并上报剂量 在胰腺癌中检测T-VEC，剂量与黑色素瘤常规使用的剂量相同。 T-VEC通过直接溶瘤和二次免疫激活来杀死肿瘤细胞。精确 免疫原性的机制在很大程度上是未知的。临床前模型显示局部和 全身抗肿瘤免疫，而坊间人类研究表明，TME的改变与增加 CD8+T细胞浸润，CD4+Foxp3+调节性T细胞数量减少。TME中的精确变化 目前尚不清楚T-VEC是否能诱导对癌症抗原的系统免疫。 这项研究是哥伦比亚大学和约翰霍普金斯医学院以及 目标是(1)确定胰腺癌患者经内窥镜治疗的T-VEC的MTD，(2)定义变化 在局部TME中诱导T-VEC，特异性流行T细胞亚群，并(3)检测疫苗是否接种 产生针对胰腺肿瘤抗原的全身性抗体反应，并比较这些抗体 与GVAX疫苗诱导的反应，GVAX是一种分泌经照射的胰腺的GMCSF 以前发现的癌细胞株可以改变胰腺癌的TME。 。

ABSTRACT This Orphan Drug Grant application is for a phase 1 clinical trial of talimogene laherparepvec (T-VEC), an oncolytic virus administered endoscopically, in the treatment of unresectable pancreatic cancer. Advanced pancreatic cancer is unfortunately nearly universally fatal with an estimated dismal median five-year survival of 6.8% for locally advanced disease and 2.8% for patients presenting with distant metastasis. We propose an investigator-initiated study in pancreatic cancer of T-VEC, a first in class oncolytic virus approved for the treatment of melanoma. No therapy prolonging survival more than several months is currently available to pancreatic cancer patients, and the failure of immunotherapy trials to enhance survival has been attributed to the unique immunosuppressive tumor micro-environment (TME) in pancreatic cancer. Oncolytic viruses, such as T-vec, may dramatically alter the TME through release of danger signals and activation of innate immune pathways. The proposed study has been approved by the FDA (IND#17248) and was submitted to the Columbia University IRB on 11/23/2016 (IRB#AAQ9966). T-VEC was previously tested in pancreatic cancer and showed good tolerability and evidence of activity with two minor responses and one stable disease out of 7 treated patients at the highest dose tested which was a log lower than the one used in melanoma. This study was abandoned before the MTD was reached for financial reasons. We now propose to complete this study and dose escalate to test T-VEC in pancreatic cancer at the same dose routinely used in melanoma. T-VEC kills tumor cells through direct oncolysis and also through secondary immune activation. Precise mechanisms of immunogenicity are largely unknown. Pre-clinical models show enhancement in local and systemic anti-tumor immunity while anecdotal human studies suggest alteration in the TME with increased CD8+T cell infiltration and decreased numbers of CD4+Foxp3+ regulatory T cells. Precise alteration in the TME is unknown and it has not been established whether T-VECinduces systemic immunity against cancer antigens. This study is a collaborative project between Columbia University and Johns Hopkins Medical Institute and the goals are to (1) define the MTD for T-VEC administered endoscopically in pancreatic cancer, (2) define changes induced in the local TME by T-VEC, specifically prevalence of T cell subsets, and (3) test whether the vaccine produces systemic antibody responses against pancreatic tumor antigens and compare these antibody responses with those that are induced by vaccination with GVAX, a GMCSF secreting irradiated pancreatic cancer cell line previously shown to alter the TME in pancreatic cancer. .