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

摘要 这是一个孤儿药资助申请，用于Talimogene Laherparepvec（T-VEC）的1期临床试验， 在治疗不可切除的胰腺癌中，通过内窥镜给予溶瘤病毒。先进 不幸的是，胰腺癌几乎是普遍致命的，据估计， 6.8%为局部晚期疾病，2.8%为远处转移患者。我们提出了一个 胰腺癌中T-VEC的肿瘤发生器启动的研究，T-VEC是一类首次批准用于治疗的溶瘤病毒。 黑色素瘤的治疗目前没有延长生存期超过几个月的治疗方法， 胰腺癌患者，以及免疫治疗试验的失败，以提高生存已被归因于 胰腺癌中独特的免疫抑制肿瘤微环境（TME）。溶瘤病毒，如 如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。 途径。 拟议的研究已获得FDA批准（IND #17248），并提交给哥伦比亚大学 IRB于2016年11月23日（IRB#AAQ9966）。T-VEC先前在胰腺癌中进行了测试，显示出良好的 耐受性和活性证据，7例治疗患者中有2例轻微缓解和1例疾病稳定， 测试的最高剂量比黑素瘤中使用的剂量低一个对数。这项研究被放弃了 因为财政原因，在达到MTD之前。我们现在建议完成这项研究，并逐步增加剂量 在胰腺癌中测试T-VEC，剂量与常规用于黑色素瘤的剂量相同。 T-VEC通过直接溶瘤和二次免疫激活杀死肿瘤细胞。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 全身性抗肿瘤免疫，而轶事人类研究表明TME的改变， CD 8 +T细胞浸润和CD 4 + Foxp 3+调节性T细胞数量减少。TME中的精确更改 T-VEC是否诱导针对癌抗原的全身免疫还不清楚，也尚未确定。 这项研究是哥伦比亚大学和约翰霍普金斯医学研究所之间的合作项目， 目的是（1）确定胰腺癌患者经内镜给予T-VEC的MTD，（2）确定 在T-VEC诱导的局部TME中，特别是T细胞亚群的流行，以及（3）测试疫苗是否 产生针对胰腺肿瘤抗原的系统性抗体应答，并比较这些抗体 GVAX是一种分泌GMCSF的放射性胰腺炎疫苗， 先前显示改变胰腺癌中的TME的癌细胞系。 .

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. .