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

描述(申请人提供)：胰腺癌是美国癌症死亡的第四大原因，新诊断的患者的5年存活率不到5%。需要对转移性和局部晚期疾病的患者进行新的治疗。西妥昔单抗(Erbitux)是一种识别HER1酪氨酸激酶受体的单抗，该受体在70%以上的胰腺癌中过度表达。尽管对转移性胰腺癌患者使用西妥昔单抗可以导致15%的病例肿瘤消退，但这种药物对总存活率的影响一直很低。西妥昔单抗和其他治疗性抗肿瘤单抗的活性归因于它们对肿瘤细胞的直接、抗增殖和促凋亡作用。单抗的这些直接作用反映了它们抑制结构性酪氨酸激酶受体信号转导的能力。然而，肿瘤结合的单抗也可以激活带有免疫球蛋白Fc受体(R)或免疫球蛋白G的“恒定”区域的先天免疫细胞。我们的团队在体外、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大的自然杀伤(NK)细胞和单核细胞的细胞毒和细胞因子分泌来增强单抗的抗肿瘤活性。我们发现，白细胞介素21(IL-21)显著增强NK细胞对西妥昔单抗处理的胰腺癌细胞的杀伤活性，并刺激NK细胞协同产生干扰素-？以及可以诱导T细胞迁移的趋化因子。在HER1+肿瘤的小鼠移植模型中，IL-21也有效地增强了西妥昔单抗的抗肿瘤作用。我们推测，IL-21通过激活FCR激活天然免疫效应细胞，从而增强西妥昔单抗对HER1+胰腺癌细胞的抗肿瘤活性。IL-21耐受性好，临床上可用，并且作为单一药物具有活性。该提案为IL-21与西妥昔单抗联合应用于胰腺癌的治疗提供了一个必须进行的临床前研究的大纲。这项建议的具体目的是：1)。研究IL-21共刺激包被西妥昔单抗的胰腺癌细胞对NK细胞的反应。研究IL-21增强西妥昔单抗在HER1阳性肿瘤小鼠模型中诱导肿瘤消退的机制，并确定在IL-21/西妥昔单抗方案中加入细胞毒化疗是否能提高抗肿瘤活性。公共卫生相关性：该计划寻求使用人类自然杀伤细胞和小鼠肿瘤模型的体外研究来生成临床前数据，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HER1单抗(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.