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: 7575162
• 负责人: ATUL BEDI
• 金额: $ 31.16万
• 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/7575162
• 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; 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; TP53 gene; Testing; Tumor Antigens; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; 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）：预计2005年美国将有145，290例新病例和54，290例以上死亡归因于结直肠癌。大约20%的患者在初次诊断时患有转移性结肠癌，另外25%的患者最终发生远处转移。尽管联合化疗的进展改善了结局，但化疗（5-氟尿嘧啶（5-FU）/亚叶酸钙联合伊立替康或奥沙利铂）后不可切除的转移性结直肠癌患者的中位总生存期约为2年。绝大多数结直肠癌具有遗传改变[p53的丢失/失活;表皮生长因子受体（EGFR）的表达/活化增加]，其干扰响应于DNA损伤的死亡信号传导并限制化疗剂的抗肿瘤功效。我们的研究表明，化疗药物（伊立替康，奥沙利铂）诱导p53非依赖性的表达配体NKG 2D，刺激受体使用的自然杀伤（NK）细胞，？d-TCR+ T细胞和a-TCR + T细胞用于肿瘤的免疫监视。我们发现这些药物还与Apo 2配体/肿瘤坏死因子相关的凋亡诱导配体（Apo 2L/TRAIL）（NK细胞和T细胞介导的免疫细胞毒性的关键效应物）合作，以诱导结肠癌细胞的p53非依赖性凋亡。具体目标1寻求确定免疫系统在治疗结肠直肠癌的化疗剂的体内抗肿瘤功效中的作用。拟议的研究将检验DNA损伤诱导的NKG 2D配体上调增强肿瘤细胞对免疫系统的敏感性并有助于化疗药物的体内抗肿瘤功效的假设，并检查自然杀伤（NK）细胞或其他免疫效应物的累积消耗是否在多周期化疗过程中损害化疗药物的抗肿瘤功效。具体目标2将确定是否可以通过利用树突状细胞（DC）-NK细胞相互作用激活免疫系统的策略[合成CpG寡脱氧核苷酸（CpG ODN）或减毒单核细胞增生李斯特菌（LM）感染]来增强化疗的疗效。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应答。虽然CpG ODN或减毒LM可以引起抗肿瘤免疫应答，但我们的研究表明，结肠癌细胞通过EGFR诱导的生存蛋白干扰线粒体死亡信号，增强其抵抗细胞毒性免疫效应细胞攻击的能力。特定目标3将检验以下假设：靶向EGFR的单克隆抗体（西妥昔单抗）可通过将全身产生的免疫应答集中于EGFR+肿瘤细胞并使其对免疫细胞毒性敏感，增强CpG ODN或减毒LM的抗肿瘤疗效和肿瘤特异性。这项拟议的研究旨在揭示免疫系统在确定化疗反应中的工具作用，并确定是否可以使用CpG ODN或减毒LM与西妥昔单抗联合的靶向免疫治疗来改善结直肠癌对化疗的反应。