Viral oncoprotein targeted immune therapy for Merkel cell carcinoma

描述（由申请方提供）：默克尔细胞癌（MCC）是一种侵袭性多瘤病毒相关皮肤癌，发病率不断增加，5年疾病相关死亡率为46%。尽管这种对健康的影响越来越大，但很少有临床试验关注这种独特的疾病，也不存在靶向治疗。2008年发现的默克尔细胞多瘤病毒（MCPyV）参与了约80%的MCC肿瘤的发病机制。MCC通常需要免疫原性多瘤病毒肿瘤抗原（T-Ag）癌蛋白的持续表达才能生长和存活，使其成为免疫治疗的理想靶点。 有几条证据表明免疫功能在MCC中的重要性。具有严重T细胞功能障碍的患者的MCC风险增加10至30倍，并且他们的MCC有时会在免疫功能改善后自发消退。我们以前已经证明，无论疾病的程度如何，肿瘤内CD 8 + T细胞浸润与良好的生存率相关。尽管T细胞免疫抑制与MCC风险增加相关，但>90%的MCC患者没有已知的免疫抑制，表明局部免疫抑制在肿瘤微环境中的作用。事实上，我们最近发现大多数MCC肿瘤具有显著的I类HLA下调，这是一种已知的允许肿瘤细胞通过逃避CD 8 + T淋巴细胞来逃避宿主免疫监视的机制。我们已经证明，肿瘤内注射干扰素或单次放射治疗可以逆转MCC中HLA-I的下调。MCC中病毒癌蛋白的持续表达与免疫逃避机制的可逆性相结合，为开发这种通常致命的癌症的合理治疗提供了令人兴奋的机会。 Nghiem，Koelle，Yee和Chapuis博士之间的合作导致了第一个MCC患者与MCPyV特异性多克隆T细胞联合HLA-I上调佐剂的治疗。反应包括显著的肿瘤缩小、高于基线数倍的MCPyV特异性T细胞的持续存在以及T细胞输注后100天内改善的抗原特异性T细胞反应。在目的1中，I/II期试验将检查在HLA-I上调预处理后输注的具有所需特异性/表型的多克隆抗病毒T细胞治疗的安全性和功效。大量MCPyV肽-HLA四聚体的可用性将允许多克隆抗病毒T细胞扩增，然后在体内追踪。虽然非常有前途，目前可行，过继性T细胞治疗是昂贵的和患者特异性。在目标2中，我们将开发工具并通过创建一组MCPyV特异性可溶性T细胞受体来探索未来“现成”基于重组T细胞受体的疗法的潜力。这些通用工具将用于确定MCC细胞上病毒肽/HLA复合物的基线和诱导表达，并且可以容易地开发成用于刺激性细胞因子、放射性发射体或新兴疗法的肿瘤靶向递送载体。

DESCRIPTION (provided by applicant): Merkel cell carcinoma (MCC) is an aggressive, polyomavirus-associated skin cancer with an increasing incidence and a 5-year disease-associated mortality of 46%. Despite this growing health impact, very few clinical trials have focused on this unique disease and no targeted therapies exist. The Merkel cell polyomavirus (MCPyV), discovered in 2008, is involved in the pathogenesis of approximately 80% of MCC tumors. MCC typically requires persistent expression of immunogenic polyomavirus tumor-antigen (T-Ag) oncoproteins for growth and survival, making them ideal targets for immune therapy. Several lines of evidence suggest the importance of immune function in MCC. Patients with profound T-cell dysfunction have 10- to 30-fold increased MCC risk and their MCC sometimes spontaneously regresses following improvement in immune function. We have previously demonstrated that intratumoral CD8+ T cell infiltration is associated with excellent survival regardless of extent of disease at presentation. Although T cell immunosuppression is associated with increased MCC risk, >90% of MCC patients have no known immune suppression, suggesting a role for local immunosuppression in the tumor microenvironment. Indeed, we have recently found that most MCC tumors have prominent down-regulation of class-I HLA, a known mechanism for allowing tumor cells to escape host immunosurveillance by evading CD8+ T lymphocytes. We have shown that HLA-I down-regulation can be reversed in MCC by intratumoral interferon injection or by a single dose of radiation. Ongoing expression of viral oncoproteins combined with reversibility of immune evasion mechanisms in MCC present exciting opportunities to develop rational therapy for this often-lethal cancer. Collaborations between Drs. Nghiem, Koelle, Yee, and Chapuis have resulted in treatment of the first MCC patient with MCPyV-specific polyclonal T cells in conjunction with HLA-I up-regulating adjuvants. Responses include significant tumor shrinkage, persistence of MCPyV-specific T cells at several-fold above baseline, and improved antigen-specific T cell responses over 100 days after T cell infusion. In Aim 1, a phase I/II trial will examine the safety and efficacy of therapy with polyclonal antiviral T cells of a desired specificity/phenotype infused following HLA-I up-regulating pre-treatment. Availability of a large panel of MCPyV peptide-HLA tetramers will allow polyclonal antiviral T cells to be expanded and then tracked in vivo. Although highly promising and currently feasible, adoptive T cell therapy is costly and patient-specific. In Aim 2, we will develop tools and explore the potential for future "off-the-shelf" recombinant T cell receptor-based therapies by creating a panel of MCPyV-specific soluble T cell receptors. These versatile tools will be used to determine the baseline and induced expression of viral peptide/HLA complexes on MCC cells and could be readily developed into tumor-targeted delivery vehicles for stimulatory cytokines, radioactivity emitters, or emerging therapeutics.