BETR Therapy for Herpesvirus-Associated Tumors

BETR 治疗疱疹病毒相关肿瘤

• 批准号: 7784032
• 负责人: RICHARD Frederick AMBINDER
• 金额: $ 58.24万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7784032
• 关键词: Affect; Aggressive course; Animal Model; B-Cell Lymphomas; B-Lymphocytes; Beta Particle; Bortezomib; Burkitt Lymphoma; Carcinoma; Cause of Death; Cell surface; Cells; Clinic; Drug Kinetics; EBV-associated malignancy; Effectiveness; Enzymes; Ganciclovir; Genes; Genome; Herpes Simplex Infections; Herpesviridae; Hodgkin Disease; Human Herpesvirus 4; Image; Infection; Investigation; Lead; Libraries; Lymphoma; Lytic Phase; MS4A1 gene; Malignant Neoplasms; Mediating; Metabolic; Molecular; Molecular Weight; Monoclonal Antibodies; Morbidity - disease rate; Nasopharynx Carcinoma; Nose; Organ; Outcome; Patients; Peripheral; Phosphorylation; Positron-Emission Tomography; Radiation; Radiation therapy; Radioimmunoconjugate; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Refractory; Relapse; Relative (related person); Stomach; Substrate Specificity; T-Cell Lymphoma; Targeted Radiotherapy; Techniques; Testing; Therapeutic; Therapeutic Studies; Thymidine Kinase; Time; Tissues; Toxic effect; Translating; Tumor Tissue; Velcade; Viral; Viral Genome; Virus; Y 90 Ibritumomab Tiuxetan; base; cancer imaging; cell type; chimeric antibody; design; dosimetry; fialuridine; gene therapy; improved; iodine-131-tositumomab; killings; malignant stomach neoplasm; mortality; neoplastic cell; novel strategies; older patient; pilot trial; prospective; public health relevance; radiotracer; rituximab; success; thymidine kinase 1; tositumomab; tumor; uptake

DESCRIPTION (provided by applicant): Great strides have been made in the management of lymphoma with therapies tailored to particular cell types, e.g., those expressing the B cell surface molecule CD20. Monoclonal antibodies and radioimmunoconjugates such as [131I]Tositumomab (Bexxar") and [90Y]ibritumomab iuxetan (Zevalin") have led to therapeutic successes with less therapy-associated morbidity and mortality. Nevertheless, lymphoma is the cause of death for at least 20,000 people annually in the US, providing impetus for the search for new approaches to target tumor cells selectively. Since its discovery in association with Burkitt's lymphoma, Epstein-Barr Virus (EBV) has been found in association with a variety of lymphomas and other tumors, including gastric and nasopharyngeal carcinoma. Some of these lymphomas are among the very most refractory to standard therapies. Nasal-type NK lymphoma, EBV-associated peripheral T cell lymphoma and EBV-associated Hodgkin's lymphoma in older patients stand out from other lymphomas for their aggressive courses. We propose a radionuclide-based therapy for EBV-associated malignancies that relies on the metabolic concentration of a radiolabeled low molecular weight substrate in tumors mediated by the EBV thymidine kinase (TK). The approach that we will employ is also in analogy with ganciclovir-based gene therapy, except that we can omit the gene tagging step because tumor cells harboring the EBV genome will already possess the TK that we can harness for targeted, enzymatic radiotherapy. Because the substrate specificity for the viral TK is orthogonal to that of cellular TK, we can use a radiotherapeutic version of the virus-specific TK substrate, 2'-fluoro-2'-deoxy-1-2-D-arabinofuranosyl-5-iodouracil (FIAU), to effect this therapy. Because the viral genome is latent, it must be activated using a pharmacologic inducer such as bortezomib. We have already successfully administered [124I]FIAU to patients with infection for imaging non-cellular (bacterial) TK and have already determined, from a library of over 3,000 tested compounds, that bortezomib (Velcade) was most potent at activating the viral lytic cycle, and therefore TK, within infected cells. We have recently shown in animal models that Bortezomib-induced Enzyme-Targeted Radiotherapy (BETR) was capable of halting the progression of or eliminating EBV-associated tumors. Here we will translate this promising experimental technique to the clinic by performing careful dosimetry studies, using FIAU-PET, which will be used to guide an initial therapeutic study in lymphoma. We anticipate that this enzyme-mediated molecular radiotherapy, which we will use here to treat herpesvirus-associated tumors, will encourage further investigation into the activation of tissue-specific enzymes for cancer imaging and therapy. PUBLIC HEALTH RELEVANCE: Certain cancers, including lymphoma, nasopharyngeal carcinoma, gastric cancer and others, are often associated with viruses, in particular, the Epstein-Barr virus (EBV). We can harness an enzyme produced by EBV, the viral thymidine kinase (TK), to effect a new type of targeted therapy that employs a radiotherapeutic version of the viral TK substrate, namely, [131I]FIAU. Because EBV is often latent within the tumor, it must be activated by treatment with bortezomib. We will treat patients with EBV-associated lymphoma and nasopharygeal carcinoma with bortezomib then image them with [124I]FIAU and positron emission tomography, using the imaging to guide treatment with [131I]FIAU. This is a prospective, pilot trial of Bortezomib-induced Enzyme-Targeted Radiation (BETR) therapy in patients with relapsed/refractory EBV-associated malignancy.

描述(由申请人提供)： 针对特定细胞类型(例如，表达B细胞表面分子CD20的细胞)的治疗在淋巴瘤的治疗方面取得了很大进展。单抗和放射免疫结合物如[131I]Tositumomab(Bexxar“)和[90Y]ibritumomab iuxetan(Zvalin”)已导致治疗成功，与治疗相关的发病率和死亡率较低。然而，在美国，每年至少有2万人死于淋巴瘤，这为寻找选择性靶向肿瘤细胞的新方法提供了动力。自从发现与Burkitt淋巴瘤有关以来，EB病毒(EBV)已被发现与多种淋巴瘤和其他肿瘤有关，包括胃癌和鼻咽癌。其中一些淋巴瘤是标准疗法最难治的。老年患者的鼻型NK淋巴瘤、EBV相关外周T细胞淋巴瘤和EBV相关霍奇金淋巴瘤因其侵袭性而与其他淋巴瘤脱颖而出。我们提出了一种基于放射性核素的治疗EBV相关恶性肿瘤的方法，该方法依赖于EBV胸苷激酶(TK)介导的放射性标记低分子底物在肿瘤中的代谢浓度。我们将采用的方法也类似于基于更昔洛韦的基因治疗，除了我们可以省略基因标记步骤，因为携带EBV基因组的肿瘤细胞已经拥有TK，我们可以利用TK进行靶向、酶促放射治疗。由于病毒TK的底物特异性与细胞TK的底物特异性是正交的，我们可以使用病毒特异性TK底物的放射治疗版本2‘-fluoro-2’-deoxy-1-2-D-arabinofuranosyl-5-iodouracil(FIAU)来实现这种治疗。因为病毒基因组是潜伏的，所以必须使用药物诱导剂激活它，如Bortezomib。我们已经成功地对感染患者进行了[124I]FIAU的非细胞(细菌)TK成像，并已经从3000多种测试化合物库中确定，Bortezomib(VELCADE)在激活感染细胞内的病毒裂解循环方面最有效，因此TK也最有效。我们最近在动物模型中证明，Bortezomib诱导的酶靶向放射治疗(BETR)能够阻止或消除EBV相关肿瘤的进展。在这里，我们将通过使用FIAU-PET进行仔细的剂量学研究，将这项有希望的实验技术转化到临床上，这将被用于指导淋巴瘤的初步治疗研究。我们预计，我们将在这里用于治疗疱疹病毒相关肿瘤的这种酶介导的分子放射治疗，将鼓励进一步研究用于癌症成像和治疗的组织特异性酶的激活。 公共卫生相关性： 某些癌症，包括淋巴瘤、鼻咽癌、胃癌和其他癌症，往往与病毒有关，特别是爱泼斯坦-巴尔病毒(EBV)。我们可以利用EBV产生的一种酶，病毒胸苷激酶(TK)，来实现一种新型的靶向治疗，这种治疗使用了病毒TK底物的放射治疗版本，即[131I]FIAU。由于EBV在肿瘤内通常是潜伏的，它必须通过使用Bortezomib治疗而被激活。我们将用Bortezomib治疗EBV相关淋巴瘤和鼻咽癌患者，然后对他们进行[124I]FIAU和正电子发射断层扫描，以此来指导[131I]FIAU的治疗。这是一项对复发/难治性EBV相关恶性肿瘤患者进行Bortezomib诱导酶靶向放射(BETR)治疗的前瞻性先导性试验。