Using Targeted Immunotherapy to Enhance Chemotherapy of Colorectal Cancer

使用靶向免疫疗法增强结直肠癌的化疗

• 批准号: 8005558
• 负责人: ATUL BEDI
• 金额: $ 30.23万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-07 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8005558
• 关键词: Apoptosis; Attenuated; CD8B1 gene; Cancer Etiology; Cell Communication; Cessation of life; Cetuximab; Colon Carcinoma; Colorectal Cancer; Combination Drug Therapy; DNA Damage; Dendritic Cells; Diagnosis; Distant Metastasis; Effector Cell; Epidermal Growth Factor Receptor; Fluorouracil; Generations; Immune; Immune response; Immune system; Immunologic Cytotoxicity; Immunologic Surveillance; Immunotherapy; Infection; Leucovorin; Ligands; Listeria monocytogenes; Liver; Mediating; Metastatic Neoplasm to the Liver; Mitochondria; Monoclonal Antibodies; Mutation; NK Cell Activation; Natural Killer Cells; Outcome; Patients; Proteins; Research; Research Personnel; Role; Signal Transduction; T-Lymphocyte; Testing; Tumor Antigens; Tumor Necrosis Factor-alpha; Tumor-Associated Process; United States; Unresectable; Up-Regulation; cancer cell; chemotherapeutic agent; chemotherapy; cytotoxic; improved; in vivo; irinotecan; killings; metastatic colorectal; mortality; neoplastic cell; oxaliplatin; programs; receptor; response; tumor; tumor specificity

DESCRIPTION (provided by applicant): An estimated 145,290 new cases and more than 54,290 deaths attributed to colorectal cancer are expected in the United States in the year 2005. Approximately 20% of patients present with metastatic colon cancer at initial diagnosis, and another 25% ultimately develop distant metastases. Although advances in combination chemotherapy have improved outcome, median overall survival of patients with unresectable metastatic colorectal cancer following chemotherapy (5-fluorouracil (5-FU)/leucovorin with either irinotecan or oxaliplatin) is approximately 2 years. The vast majority of colorectal cancers harbor genetic alterations [loss/inactivation of p53; increased expression/activation of the epidermal growth factor receptor (EGFR)] that interfere with death signaling in response to DNA damage and limit the antitumor efficacy of chemotherapeutic agents. Our studies indicate that chemotherapeutic agents (irinotecan, oxaliplatin) induce p53-independent expression of ligands for NKG2D, a stimulatory receptor used by natural killer (NK) cells, ?d-TCR+ T cells and a¿-TCR+ T cells for immune surveillance of tumors. We find that these agents also cooperate with Apo2 Ligand/ Tumor necrosis factor- related apoptosis-inducing ligand (Apo2L/TRAIL), a key effector of NK cell- and T cell-mediated immunologic cytotoxicity, to induce p53-independent apoptosis of colon cancer cells. Specific Aim 1 seeks to establish a role of the immune system in the in vivo antitumor efficacy of chemotherapeutic agents in the treatment of colorectal cancers. The proposed studies will test the hypothesis that DNA damage-induced upregulation of NKG2D ligands enhances the sensitivity of tumor cells to the immune system and contributes to the in vivo antitumor efficacy of chemotherapeutic agents, and examine whether the cumulative depletion of natural killer (NK) cells or other immune effectors during the course of multi-cycle chemotherapy impairs the antitumor efficacy of chemotherapeutic agents. Specific Aim 2 will determine whether the efficacy of chemotherapy can be enhanced via strategies that exploit dendritic cell (DC)-NK cell interactions to activate the immune system [synthetic CpG oligodeoxynucleotides (CpG ODN) or infection with attenuated Listeria Monocytogenes (LM)]. Our premise is that DC-NK cell crosstalk may not only harness the innate immune system to improve the efficacy of chemotherapy, but also facilitate the generation of long-lasting adaptive immune responses to tumor antigens that are generated in the process of tumor killing. Although CpG ODN or attenuated LM can elicit antitumor immune responses, our studies indicate that colon cancer cells enhance their ability to withstand an attack by cytotoxic immune effector cells via EGFR-induced survival proteins that interfere with mitochondrial death signaling. Specific Aim 3 will test the hypothesis that a monoclonal antibody targeting EGFR (cetuximab) can enhance the antitumor efficacy and tumor-specificity of CpG ODN or attenuated LM by focusing systemically generated immune responses to EGFR+ tumor cells and sensitizing them to immunologic cytotoxicity. The proposed research seeks to uncover an instrumental role of the immune system in determining responses to chemotherapy and determine whether targeted immunotherapy with either CpG ODN or attenuated LM in combination with cetuximab can be used to improve the response of colorectal cancers to chemotherapy.

描述（由申请人提供）：2005年美国预计将有145,290例新病例和超过54290例结直肠癌死亡。大约20%的患者在最初诊断时表现为转移性结肠癌，另外25%的患者最终发展为远处转移。尽管联合化疗的进展改善了预后，但化疗（5-氟尿嘧啶(5-FU)/亚叶酸蛋白联合伊立替康或奥沙利铂）后不可切除转移性结直肠癌患者的中位总生存期约为2年。绝大多数结直肠癌存在遗传改变[p53的缺失/失活；表皮生长因子受体（EGFR）的表达/激活增加，该受体在DNA损伤反应中干扰死亡信号并限制化疗药物的抗肿瘤效果。我们的研究表明，化疗药物（伊立替康，奥沙利铂）诱导p53不依赖于NKG2D配体的表达，NKG2D是一种自然杀伤（NK）细胞使用的刺激受体。d-TCR+ T细胞和a -TCR+ T细胞对肿瘤的免疫监测。我们发现这些药物还与Apo2配体/肿瘤坏死因子相关凋亡诱导配体（Apo2L/TRAIL）合作，诱导p53非依赖性结肠癌细胞凋亡，Apo2L/TRAIL是NK细胞和T细胞介导的免疫细胞毒性的关键效应物。特异性目的1旨在建立免疫系统在化疗药物治疗结直肠癌的体内抗肿瘤疗效中的作用。本研究将验证DNA损伤诱导的NKG2D配体上调可增强肿瘤细胞对免疫系统的敏感性，促进化疗药物体内抗肿瘤疗效的假说，并检验在多周期化疗过程中自然杀伤（NK）细胞或其他免疫效应器的累积耗竭是否会损害化疗药物的抗肿瘤疗效。特异性目的2将确定是否可以通过利用树突状细胞(DC)-NK细胞相互作用来激活免疫系统的策略来增强化疗的疗效[合成CpG寡脱氧核苷酸（CpG ODN）或感染减毒单核增生李斯特菌（LM）]。我们的前提是DC-NK细胞串扰不仅可以利用先天免疫系统来提高化疗的疗效，而且还可以促进对肿瘤杀伤过程中产生的肿瘤抗原产生持久的适应性免疫反应。虽然CpG ODN或减毒LM可以引发抗肿瘤免疫反应，但我们的研究表明，结肠癌细胞通过egfr诱导的存活蛋白干扰线粒体死亡信号，增强了它们抵御细胞毒性免疫效应细胞攻击的能力。特异性Aim 3将验证一个假设，即靶向EGFR的单克隆抗体（西妥昔单抗）可以通过聚焦系统产生的对EGFR+肿瘤细胞的免疫应答并使其对免疫细胞毒性敏感，从而增强CpG ODN或减毒LM的抗肿瘤功效和肿瘤特异性。拟议的研究旨在揭示免疫系统在决定化疗反应中的重要作用，并确定CpG ODN或减毒LM联合西妥昔单抗的靶向免疫治疗是否可用于改善结直肠癌对化疗的反应。