BETR Therapy for Herpesvirus-Associated Tumors

描述（由申请人提供）： 在淋巴瘤的管理中已经取得了巨大的进步，治疗方法针对特定的细胞类型，例如，表达B细胞表面分子CD 20的那些。单克隆抗体和放射性免疫缀合物如[131 I]托西莫单抗（Bexxar”）和[90 Y]替伊莫单抗（Zevalin”）已导致治疗成功，治疗相关的发病率和死亡率较低。然而，淋巴瘤是美国每年至少20，000人死亡的原因，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EB病毒与伯基特淋巴瘤相关以来，已发现EB病毒与多种淋巴瘤和其他肿瘤（包括胃癌和鼻咽癌）相关。这些淋巴瘤中的一些是标准疗法最难治的。鼻型NK淋巴瘤、EBV相关外周T细胞淋巴瘤和EBV相关霍奇金淋巴瘤在老年患者中因其侵袭性病程而从其他淋巴瘤中脱颖而出。我们提出了一种基于放射性核素的治疗EBV相关的恶性肿瘤，依赖于由EBV胸苷激酶（TK）介导的肿瘤中放射性标记的低分子量底物的代谢浓度。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，我们可以利用这些TK进行靶向酶放射治疗。由于病毒TK的底物特异性与细胞TK的底物特异性正交，我们可以使用病毒特异性TK底物的放射性形式，2 '-氟-2'-脱氧-1-2-D-阿拉伯呋喃糖基-5-碘尿嘧啶（FIAU）来实现这种治疗。由于病毒基因组是潜伏的，必须使用药理学诱导剂如硼替佐米来激活。我们已经成功地将[124 I]FIAU用于感染患者的非细胞（细菌）TK成像，并且已经从超过3，000种测试化合物的库中确定，硼替佐米（万珂）在激活病毒裂解周期方面最有效，因此在感染细胞内激活TK。我们最近在动物模型中表明，硼替佐米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进行仔细的剂量测定研究，将这种有前途的实验技术转化为临床，这将用于指导淋巴瘤的初步治疗研究。我们预计，这种酶介导的分子放射治疗，我们将在这里使用治疗疱疹病毒相关的肿瘤，将鼓励进一步研究组织特异性酶的激活，用于癌症成像和治疗。 公共卫生相关性： 某些癌症，包括淋巴瘤、鼻咽癌、胃癌等，通常与病毒有关，特别是EB病毒（EBV）。我们可以利用EBV产生的酶，病毒胸苷激酶（TK），来实现一种新型的靶向治疗，该治疗采用病毒TK底物的放射性版本，即[131 I]FIAU。由于EBV通常潜伏在肿瘤内，因此必须通过硼替佐米治疗来激活它。我们将用硼替佐米治疗EBV相关淋巴瘤和鼻咽癌患者，然后用[124 I]FIAU和正电子发射断层扫描对其进行成像，使用成像指导[131 I]FIAU治疗。这是一项硼替佐米诱导的酶靶向放射（BETR）治疗复发/难治性EBV相关恶性肿瘤患者的前瞻性初步试验。

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.