Improving Vaccinia for Peritoneal Tumors: Enhanced Distribution & Immune Evasion

改善腹膜肿瘤痘苗：增强分布

• 批准号: 8192269
• 负责人: DAVID L BARTLETT
• 金额: $ 31.33万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8192269
• 关键词: Abdominal Pain; Address; Affect; Antibodies; Ascites; Biological Assay; Blood Circulation; Breathing; CCL19 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Patient; Cell surface; Cells; Cessation of life; Clinical; Clinical Management; Clinical Trials; Colon; Cytotoxic T-Lymphocytes; Deposition; Distant; Dose; Engineering; Enzyme-Linked Immunosorbent Assay; Genes; Goals; Greater sac of peritoneum; IL17 gene; IL4 gene; Immune; Immune response; Immunity; Immunocompetent; Immunofluorescence Immunologic; Immunologics; Individual; Infection; Injection of therapeutic agent; Interleukin-10; Intestinal Obstruction; Knockout Mice; Lead; Leucocytic infiltrate; Leukocytes; Life; Lymphocyte; Malignant Neoplasms; Measures; Mediating; Membrane; Mesothelioma; Modeling; Mus; Mutate; Mutation; Normal tissue morphology; Oncolytic; Ovarian; Parents; Pathogenicity; Patients; Peritoneal; Phenotype; Poxviridae; Proteins; RANTES; Recovery; Resistance; Safety; Seeds; Site; Surface; T cell response; Testing; Therapeutic; Time; Tumor Tissue; Vaccinia; Vaccinia virus; Vaccinium; Viral; Virus; Vomiting; arm; cancer cell; cellular imaging; chemokine; chemotherapy; clinical application; effective therapy; extracellular; immune clearance; immune function; improved; in vitro Model; in vivo; interest; intraperitoneal; killings; monocyte; mouse model; mutant; neutralizing antibody; novel; novel strategies; novel therapeutics; premature; programs; response; success; treatment strategy; tumor

DESCRIPTION (provided by applicant): Novel treatments are warranted for peritoneal surface malignancies (including colon, ovarian, appendiceal, and mesothelioma). We have a comprehensive program for the clinical management of patients with peritoneal surface malignancies and are exploring new therapeutic options. We also have a long standing interest in poxviruses for oncolytic viral therapy, and we previously developed a tumor-selective, replicating oncolytic vaccinia virus for clinical use (vvDD). While vvDD has demonstrated success as a direct injection into patients' tumors, it is limited by the patient's premature immune mediated clearance of the virus. We propose in this project to enhance this vaccinia virus for the treatment of peritoneal tumors, addressing the limitation of premature immune clearance of the virus. We recently discovered that the expression of chemokines, CCL5 or CCL19, leads to prolonged, selective replication in the tumor microenvironment, however, in the normal tissues the chemokine-expressing virus is cleared rapidly. We hypothesize that the CKs (CCL5 or CCL19) secreted from poxvirus-infected cancer cells in the tumor have attracted from circulation a large amount of naive leukocytes including monocytes and lymphocytes. These cells in the tumor microenvironment initiate and sustain strong type 2 immune responses which enable the CCL5 (or CCL19)-expressing virus to persist in the tumor. Pre-existing anti-poxviral immunity also affects the efficacy of vvDD. We have recently demonstrated that an A34R mutation enhances the release of an enveloped form (EEV) of the virus, which may not be recognized by neutralizing antibodies. The A34R mutation has the additional advantage of releasing large quantities of virus from the cell, enhancing the spread of the virus to distant sites. This is especially important in the setting of peritoneal spread, where it is common to have thousands of individual tumor deposits. Thus, we hypothesize that our tumor-selective vvDD, when engineered with an A34R mutation and the appropriate chemokine expression, will result in improved treatment of peritoneal surface malignancies, and overcome important limitations encountered in our clinical trial. Our aims are: (1) Characterize the extent and mechanism of prolonged vvDD replication in vivo when expressing CCL5 and/or CCL19 chemokines, (2) Define the mechanism of prolonged viral replication using in vitro modeling, and gene knockout mouse models, and (3) Arming vvDD with the ability to evade the pre-exisiting anti-poxviral immunity and spread widely throughout the peritoneal cavity, by mutating the A34R gene. With these aims we are confident that we will overcome some of the obstacles to successful viral therapy and be able to move forward with a new clinical trial for patients with peritoneal surface malignancies. The information obtained regarding the immune consequences of chemokine expression in the tumor microenvironment will be important for all viral therapies. The significance of the A34R deletion with enhanced release of the vvDD will be important for all poxvirus clinical applications. PUBLIC HEALTH RELEVANCE: The overall goal of this proposal is to enhance the application of oncolytic, replication- selective vaccinia virus to treat peritoneal surface malignancies, using an A34R mutation and chemokine (CCL5, CCL19) expression. The survival of patients with these tumors is measured in months, and no effective strategies for treatment exist. Patients suffer greatly, with abdominal pain, vomiting, bowel obstruction, ascites, difficulty breathing, inanition and ultimately death. Successful intraperitoneal vaccinia therapy has the potential to improve quality and duration of life, with the chance for long term survival. Understanding the mechanism of action and significance of A34R mutation and the effects of chemokine expression will benefit all types of viral therapies.

描述（由申请人提供）：应对腹膜表面恶性肿瘤（包括结肠，卵巢，阑尾和间皮瘤）进行新的治疗方法。我们有一个综合计划，用于对腹膜表面恶性肿瘤患者的临床管理，并正在探索新的治疗选择。我们也对肺毒病毒治疗的痘病毒具有很长的兴趣，并且我们以前开发了一种肿瘤选择性的，重复溶瘤疫苗供临床使用（VVDD）。尽管VVDD已直接注射患者肿瘤，但它受到患者过早的免疫介导的病毒清除率的限制。我们在该项目中建议增强该疫苗病毒治疗腹膜肿瘤，以解决该病毒过早免疫清除率的局限性。我们最近发现，趋化因子CCL5或CCL19的表达导致肿瘤微环境中延长的选择性复制，但是，在正常组织中，表达趋化因子的病毒的表达迅速被清除。我们假设肿瘤中从痘病毒感染的癌细胞分泌的CKS（CCL5或CCL19）因循环吸引了大量幼稚白细胞，包括单核细胞和淋巴细胞。肿瘤微环境中的这些细胞启动并维持强大的2型免疫反应，从而使CCL5（或CCL19）表达病毒能够持续存在于肿瘤中。现有的抗氧化病毒免疫也会影响VVDD的功效。我们最近证明，A34R突变增强了病毒的包膜形式（EEV）的释放，这种抗体可能无法通过中和抗体来识别。 A34R突变具有从细胞中释放大量病毒的附加优势，从而增强了病毒到远处的扩散。这在腹膜蔓延的情况下尤其重要，那里通常拥有成千上万个单个肿瘤沉积物。因此，我们假设我们的肿瘤选择性VVDD在使用A34R突变和适当的趋化因子表达进行工程时，将改善腹膜表面恶性肿瘤的治疗，并克服我们临床试验中遇到的重要限制。我们的目的是：（1）表征体内长时间VVDD复制的程度和机制在表达CCL5和/或CCL19趋化因子时（2）定义了使用体外建模和基因敲除模型以及（3）与Excienty to-evade to-evide to-exiSIS to-exiSISIS to-exied to-exifian to-exifian to-evir to的机制，以及（3）持续量的病毒复制机制，以及（3）腹膜腔，通过突变A34R基因。有了这些目标，我们相信我们将克服成功的病毒疗法的一些障碍，并能够为腹膜表面恶性肿瘤患者进行新的临床试验。获得有关肿瘤微环境中趋化因子表达的免疫后果的信息对于所有病毒疗法都​​很重要。 A34R缺失随增强VVDD的释放的重要性对于所有痘病毒临床应用都很重要。 公共卫生相关性：该提案的总体目标是使用A34R突变和趋化因子（CCL5，CCL19）表达来增强溶瘤，复制 - 选择性疫苗病毒治疗腹膜表面恶性肿瘤的应用。这些肿瘤患者的存活时间数月以几个月的形式进行测量，并且没有有效的治疗策略。患者遭受腹部疼痛，呕吐，肠梗阻，腹水，呼吸困难，侵害和最终死亡的痛苦。成功的腹膜内乳房疗法有可能改善质量和寿命，并有可能长期生存。了解A34R突变的作用机理和重要性以及趋化因子表达的作用将使所有类型的病毒疗法受益。