Novel cellular immunotherapies for solid tumors
Dr. Courtney Crane’s laboratory is developing a novel cellular therapy using a circulating macrophage precursor known as a monocyte as a tissue resident, persistent, non-proliferating source of several types of protein products using ex vivo lentiviral modification. These include, but are not limited to, full-length antibodies, orthogonal and chimeric surface receptors, cytokines, and chemokines. The process results in nearly 100% of the cells expressing the gene of interest, eliminating the need for subsequent selection of transduced cells. When injected into animal models of intracranial tumors, locally injected cells persist and maintain gene expression for the duration of the studies we have performed (to date, approximately 40 days). Initial work aims to overcome immune suppression in the solid tumor microenvironment using immune stimulating protein production and local delivery of engineered macrophages, but may also synergize with other types of immune based therapies, including adoptive CAR-T cells, checkpoint blockades, and small molecules or peptides.
Current studies are evaluating the intravenous delivery and homing of macrophages to tumor tissue. Data from the lab demonstrate that following intravenous injection, macrophages rapidly accumulate in the lung followed by dispersion of a subset of macrophages to tumor tissue within 7 days, and may therefore be useful in targeting unresectable, metastatic, or multifocal tumors.
Engineered macrophages may also be edited using Cas9/CRISPR mediated gene editing with the intent to create an allogeneic product that may be administered to a number of individuals within minutes of exposure, regardless of donor or recipient haplotype. Although research models currently explore the potential of this cell therapy in oncology, the flexibility and diversity of the genes produced may allow engineered macrophages to be appropriate for a number of indications such as autoimmunity, enzyme replacement, or regenerative medicine.
Other areas of research include improving our understanding of how disease states and microenvironments influence the phenotypes and functions of circulating myeloid cells. The aim of this work is to inform patient treatment in real time, serve as disease biomarkers, or determine any impact on disease pathology and therefore serve as novel therapeutic targets.
Stage of Development
- Collaborative research opportunity
- Sponsored research agreement
- Consultation agreement
- Moyes KW, Lieberman NA, Kreuser SA, Chinn H, Winter C, Deutsch G, Hoglund V, Watson R, Crane CA. Genetically engineered macrophages: A potential platform for cancer immunotherapy. Human gene therap. 2017; 28: 200-215.
- Crane CA, Austgen K, Haberthur K, Hofmann C, Moyes KW, Avanesyan L, Fong L, Campbell MJ, Cooper S, Oakes SA, Parsa AT, Lanier LL. Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients. Proc Natl Acad Sci U S A. 2014; 111:12823-8.
- Bloch O, Crane CA, Kaur R, Safaee M, Rutkowski MJ, Parsa AT. Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages. Clin Cancer Res. 2013; 19: 3165-75.
- Genetic Engineering of Macrophages SCRI.101 , Serial # 62/216,224
To learn more about partnering with Seattle Children’s Research Institute on this or other projects, please contact:
Dr. Elizabeth Aylward, Director
Office of Science-Industry Partnerships
Seattle Children's Research Institute
818 Stewart St, Suite 603, M/S 818-S
Seattle, WA 98101