Immunobiology and immunotherapy of pancreatic cancer

描述(由申请人提供)：免疫系统可以对肿瘤生长产生积极或消极的影响，这一点被广泛接受。在许多情况下，肿瘤产生免疫抑制的微环境，有助于肿瘤逃避免疫破坏，特别是在胰腺导管腺癌(PDA)中。我们之前已经证明，CD40激动剂可以改变肿瘤微环境，并在人类和基因工程小鼠中引发巨噬细胞依赖的PDA破坏。此外，使用一种新的遗传谱系追踪方法，我们现在有了初步数据，侵袭行为和其他转移级联因素发生在疾病的最早阶段，并受到炎症的严格调控。因此，我们假设，靶向PDA的免疫抑制机制将为这种原本无法治疗的疾病提供新的治疗方法。特别是，我们假设CD40的激活可以对巨噬细胞和T细胞进行再教育，以触发原发PDA肿瘤的消退，并与免疫系统的其他成分一起阻止转移扩散。我们的最终目标是基于对肿瘤微环境中免疫调节网络的了解，设计出治疗PDA的新疗法。这项建议使用多PI机制，并将包括小鼠模型和人类患者。其具体目的是：(1)了解激动剂CD40mAb抗肿瘤作用的免疫学机制(S)，(2)了解炎症和CD40激活对转移级联反应的影响，(3)在可切除胰腺癌的临床试验中确定CD40mAb的临床和免疫学影响。

DESCRIPTION (provided by applicant): It is widely accepted that the immune system can exert either positive or negative influences on tumor growth. In many instances, tumors create an immunosuppressive microenvironment which contributes to tumor escape from immune destruction, particularly in pancreatic ductal adenocarcinoma (PDA). We have previously demonstrated that CD40 agonists can alter the tumor microenvironment and trigger a macrophage-dependent destruction of PDA in both humans and genetically engineered mice. Moreover, using a novel genetic lineage-tracing methodology, we now have preliminary data that invasive behavior and other elements of the metastatic cascade occur at the earliest stages of disease and are critically regulated by inflammation. Thus, we hypothesize that targeting immunosuppressive mechanisms in PDA will provide novel approaches to therapy for this otherwise treatment-resistant disease. In particular, we hypothesize that CD40 activation can re-educate both macrophages and T cells to trigger regression of a primary PDA tumor and impede metastatic spread in concert with other elements of the immune system. Our ultimate goal is to devise new therapies for PDA based on an understanding of immune regulatory networks in the tumor microenvironment. This proposal uses the multi-PI mechanism and will incorporate both mouse models and human patients. Specific Aims are to: (1) Understand the immunological mechanism(s) underlying the anti-tumor effect of agonist CD40 mAb, (2) Understand how inflammation and CD40 activation influence the metastatic cascade, 3) Determine the clinical and immunological impact of CD40 mAb in a clinical trial of patients with resectable pancreatic carcinoma.