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.
In this proposal, we will investigate a novel form of immunotherapy using antibodies obtained from healthy donors against cancers arising in other individuals. We will use a mouse model of mesothelioma, and immune cells and tumor cells obtained from patients with mesothelioma, to identify the key components of this therapy. Our investigations will inform the design of an early phase clinical trial, and may identify a more effective approach to treating patients with cancer.
| Lee, Hyun-Sung; Jang, Hee-Jin; Shah, Rohan et al. (2017) Genomic Analysis of Thymic Epithelial Tumors Identifies Novel Subtypes Associated with Distinct Clinical Features. Clin Cancer Res 23:4855-4864 |
