PI: Dr. Courtney Crane
Location: Seattle Children’s Research Institute
Lentiviral engineering of macrophages to improve anti-tumor immunity
Our work with the Institute for Protein Design (IPD) would be to design membrane tethered protein structures expressed using lentiviral vectors that would help the immune system recognize brain tumor cells. We have several candidates that are of interest, although two that are currently in Dr. Baker’s pipeline include a PD-1 antagonist and an IL-2 mimetic, both that will improve immune cell activation. We have recently successfully modified primary human macrophages, and demonstrated stable and robust expression of lentivirally-encoded proteins. We have selected macrophages as therapeutic agents because 1) they are not patient restricted, and can be isolated from one healthy donor and applied to many patients, 2) the potential for creation, banking, and immediate intracranial application at the time of tumor resection, and 3) they are effectively recruited and retained in the brain tumor microenvironment. Using membrane tethered designer protein structures, we will evaluate changes in the expression of phenotypic and functional changes by engineered macrophages, changes in tumor burden, and/or improved cytotoxic effector cell functions in vitro and in vivo (assays dependent on the protein structure and its expected impact). We hypothesize that these protein structures will provide a diverse array of cost-effective engineered macrophages, with the potential to restructure the tumor microenvironment and improve responses to brain tumors. Specific advantages include temporal and spatial control of protein expression encoded by lentiviral vectors that we hope will be broadly applicable to patients with solid tumors, and serve as adjuvant therapy for patients receiving standard of care or experimental treatments, including small molecule inhibitors, mono or bi specific antibodies, and adoptive cellular therapies.