Engineering adoptive transfer cells for microenvironment-sensitive gene expression

Technical overview

Courtney CraneDr. Courtney Crane is developing novel cellular therapies for solid tumors, particularly brain cancers such as gliomas. These and other solid cancers are especially difficult to treat because they manipulate their environment to hinder immune attack. Dr. Crane’s laboratory engineers immune cells to be tissue-resident, persistent, nonproliferating sources of proteins that alter the tumor microenvironment to promote antitumor immunity. The Crane group has expertise in using lentiviral vectors to induce immune cells to produce full-length antibodies, cytokines, chemokines, and other proteins. The process results in nearly 100% of the cells expressing the gene of interest, eliminating the need for subsequent selection of transduced cells.

Dr. Crane’s group is also designing new lentiviral vector systems that control when and where proteins are expressed. These vectors sense the microenvironment and express the genes they carry only when cells encounter certain conditions. More targeted delivery of microenvironment-altering proteins could reduce treatment toxicity and side effects. Approaches for controlled expression of proteins include creating cells with customized chimeric cell-surface receptors that trigger protein expression only in response to particular local cues.

Dr. Crane’s use of immune-stimulating proteins, locally delivered by engineered immune cells, may synergize with other types of immune-based therapies to overcome immune suppression in the solid tumor microenvironment, including adoptive CAR T cells, checkpoint blockades, and small molecules or peptides. 

Dr. Crane’s group is also experienced in using Cas9/CRISPR-mediated gene editing to generate other products for indications including autoimmunity, enzyme replacement, infectious disease, and regenerative medicine. Other areas of research in the Crane lab include capitalizing on new knowledge about tumor microenvironments to identify biomarkers and therapeutic targets. Dr. Crane also has expertise with ex vivo expansion of antigen-unrestricted natural killer (NK) cells for adoptive transfer.

Stage of Development

  • Pre-clinical in vitro
  • Pre-clinical in vivo
  • Pre-clinical ex vivo
  • Clinical development

Partnering Opportunities

  • Collaborative research opportunity
  • Sponsored research agreement
  • Consultation agreement
  • Licensing agreement

Publications

Moyes KW, Davis A, Hoglund V, Haberthur K, Lieberman NAP, Kreuser SA, Deutsch GH, Franco S, Locke D, Carleton MO, Gilbertson DG, Simmons R, Winter C, Silber J, Gonzalez-Cuyar LF, Ellenbogen RG, Crane CA. Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma. OncoImmunology. 2018; doi.org/10.1080/2162402X.2018.1507668.

Lieberman NAP, DeGolier K, Haberthur K, Chinn H, Moyes KW, Bouchlaka MN, Walker KL, Capitini CM, and Crane CA. An uncoupling of canonical phenotypic markers and functional potency of ex vivo-expanded natural killer cells. Front Immunol. 2018;9:150.

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 USA 2014; 111:12823-8.

Learn More

Courtney Crane, PhD

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 Street, Suite 603
Seattle, WA 98101
206-884-1065
elizabeth.aylward@seattlechildrens.org