Cetuximab Therapy of Pancreatic Cancer: Immune Modulation with IL-21

描述（由申请人提供）：胰腺癌是美国癌症死亡的第四大原因，新诊断患者的5年生存率低于5%。对于转移性和局部晚期疾病患者，需要新的治疗方法。西妥昔单抗（爱必妥）是一种单克隆抗体（mAb），可识别在超过70%的胰腺癌中过度表达的HER 1酪氨酸激酶受体。虽然西妥昔单抗治疗转移性胰腺癌患者可导致15%的病例肿瘤消退，但该药物对总生存率的影响很低。西妥昔单抗和其他治疗性抗肿瘤mAb的活性归因于其对肿瘤细胞的直接、抗增殖和促凋亡作用。mAb的这些直接作用反映了它们抑制组成型酪氨酸激酶受体信号转导的能力。然而，肿瘤结合的mAb也可以激活携带免疫球蛋白G的Fc或“恒定”区的受体（R）的先天免疫细胞。我们的研究小组已经在体外、小鼠模型和I期临床试验中证明，激活细胞因子可以通过刺激强效自然杀伤（NK）细胞和单核细胞的细胞毒性和细胞因子分泌的能力增强mAb的抗肿瘤活性。我们发现，白细胞介素-21（IL-21）显着增强NK细胞对西妥昔单抗治疗的胰腺癌细胞的细胞毒活性，并刺激协同NK细胞产生干扰素-？以及能够诱导T细胞迁移的趋化因子。IL-21也有效增强西妥昔单抗在HER 1+癌症的鼠异种移植模型中的抗肿瘤作用。我们假设IL-21给药将通过激活先天免疫效应细胞和激活FcR增强西妥昔单抗对HER 1+胰腺癌细胞的抗肿瘤活性。IL-21耐受性良好，临床上可用，并且作为单一药剂具有活性。该提案提供了必须进行的临床前研究的概述，以便将IL-21与西妥昔单抗联合用于胰腺癌的治疗。这项建议的具体目标是：1）。表征与IL-21共刺激后NK细胞对西妥昔单抗包被的胰腺癌细胞的应答，和2）。在HER 1阳性癌症小鼠模型中，研究IL-21增强西妥昔单抗诱导肿瘤消退的机制，并确定IL-21/西妥昔单抗方案中加入细胞毒性化疗是否可改善抗肿瘤活性。 公共卫生相关性：该计划旨在使用人类自然杀伤细胞和小鼠肿瘤模型的体外研究生成临床前数据，以支持在转移性或局部晚期胰腺癌患者中使用白细胞介素-21和抗HER 1单克隆抗体（西妥昔单抗）。

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer death in the U.S. and newly diagnosed patients have a 5-year survival rate of less than 5%. New treatments for patients with metastatic and locally advanced disease are needed. Cetuximab (Erbitux) is a monoclonal antibody (mAb) that recognizes the HER1 tyrosine kinase receptor that is over-expressed in greater than 70% of pancreatic cancers. Although administration of cetuximab to patients with metastatic pancreatic cancer can lead to tumor regression in 15% of cases, the impact of this agent on overall survival has been low. The activity of cetuximab and other therapeutic anti- tumor mAbs is attributed to their direct, anti-proliferative and pro-apoptotic effects on tumor cells. These direct effects of mAbs are reflective of their ability to inhibit constitutive tyrosine kinase receptor signal transduction. However, tumor bound mAbs may also activate innate immune cells that bear receptors (R) for the Fc or "constant" region of immunoglobulin G. Our group has demonstrated in vitro, in murine models, and in phase I clinical trials that activating cytokines can enhance the anti-tumor activity of mAbs via their ability to stimulate potent natural killer (NK) cell and monocyte cytotoxicity and cytokine secretion. We found that interleukin-21 (IL-21) significantly enhanced NK cell cytotoxic activity against cetuximab-treated pancreatic cancer cells, and stimulated synergistic NK cell production of interferon-? and chemokines that could induce the migration of T cells. IL-21 was also effective in augmenting the anti-tumor effects of cetuximab in a murine xenograft model of HER1+ cancer. We hypothesize that IL-21 administration will enhance the anti-tumor activity of cetuximab against HER1+ pancreatic cancer cells via the activation of innate immune effector cells with activating FcR. IL-21 is well-tolerated, clinically available, and has activity as a single agent. This proposal provides an outline for the preclinical studies that must be performed in order for IL-21 to be employed in the setting of pancreatic cancer in combination with cetuximab. The specific aims of this proposal are: 1). To characterize the NK cell response to cetuximab-coated pancreatic cancer cells following co-stimulation with IL-21, and 2). To examine the mechanism by which IL-21 enhances cetuximab-induce tumor regression in a murine model of HER1-positive cancer and determine if the addition of cytotoxic chemotherapy to the IL-21/cetuximab regimen leads to improved anti-tumor activity. PUBLIC HEALTH RELEVANCE: The program seeks to generate pre-clinical data using in vitro studies with human natural killer cells and a murine tumor model to support the use of interleukin-21 and an anti-HER1 monoclonal antibody (cetuximab) in patients with metastatic or locally advanced pancreatic cancer.