BG34-200 Triggers Myeloid Recruitment and M1 Reprogramming to Enhance Immunotherapy for Pediatric and AYA Osteosarcoma
Abstract
For cancer patients with metastatic and advanced solid tumor disease that have failed in chemotherapy, radiation therapy, and/or surgical resection, immunotherapy such as checkpoint inhibitors are becoming an increasingly used option. Cancer immunotherapy achieves immune-mediated control of tumor growth/metastasis by mounting tumor-reactive T cell responses. However, a significant number of patients do not respond. Increasing studies have shown the non-responders’ solid tumor tissues are heavily infiltrated with immune suppressive myeloid cells, which inhibit the antitumor T-cell responses and are a major cause of failure with immunotherapy. Our research team has identified a highly novel and safe molecule, BG34-200, with a specific molecular weight and side chain structure that is isolated from the outer shell of oat. BG34-200 possesses an unusual capacity to enter myeloid immune cells and trigger functional change, thus improving T-cell responses. This novel BG34-200, was shown to be highly effective when administered intravenously in reducing pulmonary metastatic osteosarcoma (OS) in mouse models. OS is the most prevalent bone cancer affecting children and adolescent or young adults (AYA), with approximately 400 to 1,200 new cases a year in the United States. Despite aggressive combination chemotherapy and surgery, the outcome for metastatic OS remains dismal. A high proportion of OS patients develop pulmonary OS (pOS) either at the time of diagnosis (20%) or after initiation of therapy. Unfortunately, almost all of the patients who develop surgically un-resectable pOS invariably succumb to this devastating disease. As OS contains extremely complex genetic alterations, molecular targeted precision therapy has proven challenging. Recent exciting scientific development implicates the immune system as a potential important new armamentarium as a novel approach to control or reduce pOS. However, as the tumors of pOS are heavily infiltrated with immune suppressive myeloid cells, the pediatric and AYA patients with pOS do not respond to currently approved immunotherapy. Novel methods that target the function of these myeloid cells have been a focus of intense research in recent years. The BG34-200 s mechanism of action and in vivo efficacy for OS, the pathological features of pediatric OS (high level suppressive myeloid cells in tumors), and the pressing need for this rare disease, have provided strong rationale for us to proceed with a first-in-human (FIH) clinical trial. We have proposed a phase 1/2 clinical trial of BG34-200 as a single agent immunotherapy in children, AYAs with recurrent, refractory or progressive pulmonary metastatic OS to the Food and Drug Administration (FDA) and received valuable feedback. We have engaged in avid discussion with the Children’s Oncology Group (COG) OS New Agent Task Force to strategize a rapid translation of BG34-200. Based upon the feedback, we design the current canine trial study in preparation for a FIH trial. The proposed dog study has been reviewed by the FDA and discussed with the National Cancer Institute s Comparative Oncology Branch. Our scientific objective is to utilize the Department of Defense Peer Reviewed Cancer Research Program s Impact Award to complete the key and gap studies suggested by the FDA, thus to enable a FIH trial targeting OS in the next 3 years (near-term impact). This proposal brings together a multi-disciplinary team at Case Western Reserve University s Department of Biomedical Engineering, UH Rainbow Babies & Children s Hospital/Angie Fowler AYA Cancer Institute to leverage exciting science and technology for cultivating BG34-200 immune-based therapeutics. A successful execution of the proposed studies will provide key preclinical data and mechanistic knowledge into the biology of immune suppressive myeloid cells and developing BG34-200 as a novel immune-therapy agent to benefit pediatric and AYA patients with OS in clinic (Clinical Significance).
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110804
Entities
People
- Mei Zhang
Organizations
- Case Western Reserve University
- United States Army