Allogeneic antibody therapy for malignant mesothelioma

 描述(申请人提供)：肿瘤通过逃避免疫系统而发展。与自体(自体)肿瘤不同，异体(非自体)肿瘤，就像器官移植一样，在移植到免疫正常的宿主体内时会被排斥。我们为了解非自身肿瘤排斥反应的这一过程而进行的研究已经确定了 同种异体免疫球蛋白抗体(Alligic Ig G)能识别肿瘤细胞，并在产生强大的抗肿瘤免疫反应。我们发现，当异种免疫球蛋白与树突状细胞(DC)刺激剂结合并注射到包括黑色素瘤、乳腺癌、胰腺癌和肺癌在内的各种小鼠肿瘤中时，这些肿瘤被根除，几乎没有副作用。重要的是，我们发现来自健康捐赠者的抗体可以识别来自间皮瘤和肺癌手术切除患者的肿瘤细胞，这些抗体可以在体外激活抗肿瘤的人体免疫反应。这项应用的目的是获得必要的临床前数据，为未来的I期临床试验提供理论基础和可行性，该试验将设计使用同种异体免疫球蛋白治疗恶性胸膜间皮瘤。我们将使用一个成熟的间皮瘤临床前模型，以及手术切除间皮瘤患者的新鲜分离的肿瘤细胞和免疫细胞来确定这项试验的关键因素：(1)最有效的DC刺激剂，(2)最有效的免疫球蛋白来源，(3)最有效的给药途径和给药程序。为了促进这种新的基于免疫的技术快速进入临床，我们将重点评估已获得FDA批准的DC刺激剂，我们还将测试FDA批准的静脉免疫球蛋白(IVIG)的商业可用配方，这些制剂通常包含来自10,000多名捐赠者的汇集抗体。在这项研究结束时，我们将确定临床级别的同种抗体配方，该配方包含适当的DC刺激剂和一种免疫球蛋白来源，我们将为其提交IND申请进行临床试验。在目标1中，我们将在临床前、免疫学完整的恶性间皮瘤小鼠模型中测试各种DC刺激剂，然后测试这些药物激活从手术切除时新鲜获得的间皮瘤肿瘤相关DC的能力。在目标2中，我们将使用类似的人类肿瘤相关DC试验来确定最有效的免疫球蛋白(IVIG或从健康捐赠者获得的混合免疫球蛋白)，并将使用我们的小鼠模型来确定最有效的异基因免疫球蛋白注射途径(局部和静脉注射)和时间表(单周期和多周期)。我们的发现将促进对同种异体免疫球蛋白治疗实体瘤的理解，并将促进使用这种新型免疫疗法的早期、首例临床试验的设计。

 DESCRIPTION (provided by applicant): Tumors progress through evasion of the immune system. In contrast to autologous (self) tumors, allogeneic (non-self) tumors, like organ transplants, are rejected when transferred into immunologically normal hosts. Our studies performed to understand this process of non-self tumor rejection has identified a critical role for allogeneic IgG antibodies (alloIgG) in the recognition of tumor cells, and in the generation of a powerful anti- tumor immune response. We have found that when alloIgG is combined with a dendritic cell (DC) stimulant and injected into a variety of mouse tumors including melanoma, breast, pancreas and lung carcinoma, that these tumors are eradicated, with little or no side effects. Importantly, we have found that IgG antibodies from healthy donors recognize tumor cells from obtained from patients undergoing surgical resection for mesothelioma and lung cancer, and that these antibodies can activate anti-tumor human immune responses, in vitro. The objective of this application is to obtain the preclinical data necessary to provide the rationale and feasibility for a future phase I clinical trial that will be designed to use alloIgG therapy for treatment of malignant pleural mesothelioma. We will use a well-established preclinical model of mesothelioma, and freshly isolated tumor cells and immune cells from patients undergoing surgical resection of mesothelioma to determine the critical elements of this trial: (1) the most efficacious DC stimulant, (2) the most efficacious source of IgG, and (3) the most efficacious route and schedule of administration of alloIgG. To facilitate rapid translation o this novel immune-based technology into the clinic, we are focusing our appraisal of DC stimulants to agents that have been approved by the FDA, and we will also test commercially available formulations of intravenous immunoglobulins (IVIG) that are FDA-approved and generally comprise pooled IgG antibodies from more than 10,000 donors. At the conclusion of this study, we will have defined a clinical grade alloantibody formulation that comprises an appropriate DC stimulant and a source of IgG, and for which we will submit IND applications for a clinical trial. In Aim 1 we will test a variety of DC stimulants in a preclinical, immunologicall intact, mouse model of malignant mesothelioma, and then test the ability of these agents to activate tumor-associated DC freshly isolated from mesothelioma tumors, freshly obtained at the time of surgical resection. In Aim 2, we will use similar human tumor-associated DC assays to determine the most effective formulation of IgG (IVIG or pooled IgG obtained from healthy donors), and we will use our mouse model to determine the most effective route (local versus intravenous) and schedule (single versus multiple cycles) of alloIgG administration. Our findings will advance the understanding of alloIgG therapy for solid tumors, and will facilitate the design of an early phase, first-in-man, clinical trial using this novel immunotherapy.