Modulation of the gut microbiome to enhance efficacy of immunotherapy in pancreatic adenocarcinoma

摘要 胰腺导管腺癌(PDA)是男性和女性最常见的十种癌症之一。 根据CDC的数据，胰腺癌的发病率在过去的几年里以每年近1.2%的速度增长 在过去的10年里。5年生存率不到7%。尽管最近检查站封锁取得了成功- 基于人类黑色素瘤和非小细胞肺癌的单一疗法，许多PDA患者不 体验持久的临床益处。我们推测除了致癌信号和抗炎作用 作为细胞因子，微生物群在引导促肿瘤先天免疫反应中起着重要作用。我们 发现PDA与不同阶段的肠道/胰腺微生物群相关，并导致疾病 通过诱导肿瘤内免疫抑制而进展。在此STTR第1阶段提案中，我们将确定 益生菌给药在恢复与降低癌症风险相关的物种方面的作用。基座 在微生物组和PDA的前期工作的基础上，我们制作了8个细菌菌株(POC518)的鸡尾酒，这些菌株 有助于维持肠道内环境的稳定。在目标1中，我们将开发一种基于纤维素的益生菌鸡尾酒配方。 POC518。进一步在目标2中，我们将直接评估POC518制剂改善αPD-1‘S的疗效 采用两种PDA动物模型进行抗肿瘤实验。我们将监测肿瘤进展和动物存活情况， 接受αPD-1治疗的动脉导管未闭动物模型的分子肿瘤发生和瘤周免疫激活 单一疗法或与抗生素和/或益生菌联合治疗。在完成上市里程碑之际，我们 将使用微生物组定向干预策略开发和评估益生菌配方 改进基于检查站的免疫治疗。这项第一阶段研究的结果将使我们能够设计临床 与其他制药公司合作进行试验。我们坚信肠道的调节 微生物组将在胰腺癌的免疫治疗中具有重大意义。

Abstract Pancreatic ductal adenocarcinoma (PDA) is among the ten most common cancers for both men and women. According to CDC the incidence rates of pancreatic cancer have been rising by almost 1.2% each year over the last 10 years. The 5-year survival rate is less than 7%. Despite the recent success of checkpoint blockade- based monotherapy in human melanoma and non-small cell lung cancer, many PDA patients do not experience durable clinical benefit. We postulated that in addition to oncogenic signals and anti-inflammatory cytokines, the microbiome plays an important role in instructing the pro-tumoral innate immune response. We found that PDA is associated with a distinct stage specific gut/pancreatic microbiome and it drives disease progression by inducing intratumoral immune suppression. In this STTR Phase 1 proposal we will determine a role for probiotic administration to restore the species that are associated with decreased cancer risk. Based on our previous work on microbiome and PDA we have made a cocktail of 8 bacterial strains (POC518) which help to maintain gut homeostasis. In Aim 1 we will develop a cellulose based formulation of probiotics cocktail POC518. Further in In Aim 2, we will directly assess the efficacy of POC518 formulation in improving αPD-1’s anti-tumor effects using two PDA animal models. We will monitor tumor progression and animal survival, molecular oncogenesis, and peri-tumoral immune activation in the PDA animal models receiving αPD-1 monotherapy or combined therapies with antibiotics and/or probiotics. At the completion of listed milestone, we will have a developed and assessed a probiotics formulation using microbiome directed intervention strategies to improve checkpoint-based immunotherapy. Findings from this Phase I study will enable us to design clinical trials in collaboration with other pharmaceuticals companies. We strongly believe that modulation of the gut microbiome will have dramatic implications in the immunotherapies for pancreatic cancer treatment.