Overcoming Immune Checkpoint Blockade Resistance in Glioblastoma with a Novel Stem Cell Biotherapeutic

PROJECT SUMMARY iOncologi, Inc. proposes to develop iOi7, a therapy utilizing autologous, ex vivo-expanded, immunomodulatory hematopoietic stem cells (HSC), for the treatment of immune checkpoint inhibitor (ICI)-resistant glioblastoma. The goal of Phase 1 of this project is to enhance our product’s commercialization potential by transitioning from our current FDA IND-approved, open HSC manufacturing approach to a closed-circuit and scalable platform. In Phase 2 of this project, we propose to utilize this updated manufacturing system in a neoadjuvant, biomarker- driven Phase I clinical trial to evaluate iOi7’s safety and feasibility in patients with relapsed or refractory glioblastoma (rGBM). Although ICIs have demonstrated biological activity and some evidence of clinical efficacy in GBM, this disease remains universally fatal with no standard-of-care options in the relapsed setting. Our preclinical data demonstrates that resistance to blockade of the programmed death-1 (PD-1) pathway can be reversed by the intravenous administration of our HSC therapy. This effect is mediated through a remarkable reprogramming of the intratumoral immune microenvironment. The specific aims of this proposal are to: (1) optimize HSC expansion using a closed, scalable, and commercially viable production platform; (2) cross-validate HSC phenotype and function using the closed-system manufacturing protocol; (3) complete IND-enabling studies, including clinical-scale HSC manufacturing and QA/QC release testing; and (4) evaluate the safety, feasibility, and biologic effects of iOi7 in the treatment of rGBM in a Phase I neoadjuvant clinical trial. The primary outcomes of this project will be the successful establishment of a closed-circuit and scalable ex vivo HSC manufacturing platform and the completion of a Phase I clinical trial testing the safety and feasibility of delivering iOi7 to patients with rGBM. Additionally, this neoadjuvant trial will provide an opportunity for biomarker evaluation of tumor tissue samples and assessment of the biological changes induced by HSC and/or PD-1 blockade. This biomarker evaluation will be crucial in understanding the effectiveness of iOi7 therapy in rGBM patients. Upon the successful completion of the Phase I clinical trial, our team will conduct Phase II clinical studies to further evaluate the efficacy of our innovative therapy. We believe iOi7 has the potential to make a significant breakthrough in the treatment of patients with GBM as well as other ICI-resistant cancers.