Translational Research in Multiple Myeloma

描述(申请人提供)：除了同种异体移植可能的例外，多发性骨髓瘤仍然是一种无法治愈的疾病，因为对细胞毒药的泛耐药。不幸的是，由于高龄、合并疾病或广泛的既往治疗，大多数患者不符合异基因移植的条件。因此，需要新的方法来治疗这种疾病。这项提议的目的是通过将有希望的策略从实验室转化为临床来开发骨髓瘤的新临床治疗方法，并使赫夫博士能够成为多发性骨髓瘤领域的独立翻译研究员，这项职业发展提议包括在约翰霍普金斯公共卫生与卫生学院获得健康科学硕士学位的临床研究理论和方法方面的正式培训，同时还包括多发性骨髓瘤的翻译研究计划。 临床结果表明，同种异体移植中使用的细胞毒预适应方案在控制骨髓瘤方面作用有限，而与移植物抗宿主相关的免疫抗肿瘤作用似乎具有很强的抗骨髓瘤活性。因此，我们正在开发一项新的临床试验，利用非清髓性骨髓移植治疗骨髓瘤，该试验将限制预适应方案的毒性，并突出异基因移植物抗骨髓瘤的效果。基于实验室令人鼓舞的初步数据，我们计划将抗骨髓瘤疫苗纳入移植后供者淋巴细胞输注中，这是非清髓性骨髓移植的关键组成部分。 对于许多患者来说，即使是非清髓性异基因骨髓移植也是不可能的。因此，需要其他治疗方法。我们实验室的初步数据表明，细胞因子介导的分化是另一种可能的策略。骨髓瘤中有多种生长因子和细胞因子具有活性。IL-6似乎是最重要的。干扰素-显然在骨髓瘤中具有临床抗肿瘤活性，尽管其在多发性骨髓瘤治疗中的作用仍存在争议。干扰素的确切作用机制尚不清楚；然而，它的多重作用之一是通过诱导G1细胞周期停滞而产生抗增殖活性。生长因子和细胞因子对恶性生长的净作用是由它们对肿瘤细胞自我更新、存活和分化的多重作用的平衡决定的。优先增强肿瘤细胞的自我更新和/或存活可加速肿瘤进展；相反，主要或选择性的诱导分化将耗尽肿瘤克隆。我们的初步数据表明，干扰素等抑制细胞周期的药物优先增强IL-6对骨髓瘤的分化作用，并阻断其对肿瘤细胞增殖的影响。

DESCRIPTION (provided by applicant): With the possible exception of allogeneic transplantation, multiple myeloma remains an incurable illness due to pan-resistance to cytotoxic agents. Unfortunately, most patients are ineligible for allogeneic transplantation due to advanced age, comorbid illness or extensive prior therapy. As such, novel approaches are needed to treat this disease. The objective of this proposal is to develop novel clinical treatments for myeloma by translating promising strategies from the laboratory into the clinic and to enable Dr. Huff to become an independent translational investigator in the field of multiple myeloma, included in this career development proposal is formal training in the theory and methods of clinical investigation working towards a Masters of Health Science degree at the Johns Hopkins School of Public Health and Hygiene concurrent with translational research initiatives in multiple myeloma. Clinical results suggest that the cytotoxic conditioning regimen used in allogeneic transplantation plays a limited role in controlling myeloma, while the immunologic anti-tumor effect associated with graft-versus-host appears to have strong anti-myeloma activity. As such, we are developing a new clinical trial, utilizing nonmyeloablative BMT for myeloma that will limit the toxicity of the conditioning regimen and highlight the allogeneic graft-versus-myeloma effect. Based on encouraging preliminary data from the laboratory, we plan to incorporate anti-myeloma vaccines into the post-transplant donor lymphocyte infusions that are a key component of non-myeloablative BMT. For many patients, even a nonmyeloablative allo BMT will not be possible. Thus, other treatment approaches are needed. Preliminary data from our laboratory suggest that cytokine-mediated differentiation is another possible strategy. There are a variety of growth factors and cytokines which have activity in myeloma. IL-6 appears to be the most important. Interferon- clearly has clinical anti-tumor activity in myeloma, although its role in the management of multiple myeloma remains controversial. Interferon's exact mechanism of action is unknown; one of its multiple effects, however, is an anti-proliferative activity through induction of a G1 cell cycle arrest. The net effect of growth factors and cytokines on malignant growth is determined by a balance of their pleiotropic effects on tumor cell self-renewal, survival, and differentiation. The preferential enhancement of tumor cell self-renewal and/or survival could hasten tumor progression; conversely, a predominant or selective induction of differentiation would exhaust the neoplastic clone. Our preliminary data demonstrate that agents, like interferon, that inhibit cell cycling preferentially enhance the differentiation effects of IL-6 against myeloma, as well as block its effects on tumor cell proliferation.