Improved CAR T Targeting For Pediatric Solid Tumors and Modulation of CAR-T Targets in Hematological Malignancy
Creating next-generation adoptive immunotherapy for rhabdomyosarcoma and other cancers
Dr. Rimas Orentas focuses on developing immune-based approaches for treating childhood cancer. Molecular engineering of T lymphocytes using lentiviral-based gene vectors is a powerful and direct means to generate novel chimeric antigen receptor (CAR) T and T cell receptor (TCR)-engineered cells that have the ability to recognize and eliminate tumor cells.
With years of experience in both academic and industry settings, Dr. Orentas currently focuses on immunotherapy for pediatric cancers, especially solid tumors such as rhabdomyosarcoma, Ewing’s sarcoma, osteosarcoma, and neuroblastoma. His group uses genomic analysis of both tumors and T cells to improve the effectiveness of T cell-based therapy. This includes identifying new cell-surface-localized CAR T cell targets, new antibodies and receptors to bind targets on cancer cells, and factors that alter the tumor microenvironment.
The Orentas lab has developed CAR T cells that target fibroblast growth factor receptor 4 (FGFR4), which is altered in many cancers including rhabdomyosarcoma. They are now creating improved, advanced FGFR4-targeting CAR T cells through a collaboration to use advanced phage and yeast display methods to screen for new antibody-derived proteins that bind FGFR4. Strong candidates from the screen will be tested for effectiveness as CARs.
Dr. Orentas is the director for scientific integration at CureWorks, a nonprofit network of children’s hospitals focused on immunotherapy for pediatric cancers (www.CureWorks.org). The goal of Cureworks is to expand immunotherapy trials and global patient access, as well as to share data and collective expertise to advance novel cell therapies. The Ben Towne Center for Childhood Cancer Research at SCRI is a world leader in CAR T cell therapy, and is generating CAR T cells for CureWorks clinical trials in its GMP facility.
Partnerships with Dr. Orentas could include developing the new FGFR4-binding proteins into advanced FGFR4-targeting CAR T cells. He is also interested in targeting factors in the tumor microenvironment that might be manipulated to improve engineered T cell delivery into tumors, or which may extend the longevity and effectiveness of engineered T cells over time.
In a new area of research, Dr. Orentas is also screening small molecules that function as epigenetic modifiers for the ability to stabilize CD19 and CD20 on the surface of leukemia (B-ALL). Altered splicing of CD19, and down-modulation of CD22 are two distinct mechanisms by which leukemia evades elimination by CAR-T. By countering this process, CAR-T anti-leukemia effects will be optimized.
Stage of Development
- Preclinical in vivo
- Preclinical in vitro
- Preclinical ex vivo
- Collaborative research agreements
- Sponsored research agreements
- Platform testing for CAR T cell generation
- Li D, Li N, Zhang YF, Fu H, Feng M, Schneider D, Su L... Orentas RJ...Persistent polyfunctional chimeric antigen receptor T cells that target Glypican 3 eliminate orthotopic hepatocellular carcinomas in mice. Gastroenterology. 2020; Feb 11. pii: S0016-5085(20)30211-0. doi: 10.1053/j.gastro.2020.02.011. [Epub ahead of print]
- Ravanpay AC, Gust J, Johnson AJ, Rolczynski LS, Cecchini M, Chang CA, Hoglund VJ, Mukherjee R, Vitanza NA, Orentas RJ, Jensen MC. EGFR806-CAR T cells selectively target a tumor-restricted EGFR epitope in glioblastoma. Oncotarget. 2019; 10(66): 7080-7095.
- Fry T, Shah NN, Orentas RJ...CD22-CAR T Cells Induce Remissions in CD19-CAR Naïve and Resistant B-ALL. Nature Medicine. 2018; 24(1): 20-28.
- Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M...Orentas RJ...4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nature Medicine. 2015; 21: 581-590.
- Haso W, Lee DW, Shah NN, Stetler-Stevenson M, Yuan CM...Orentas RJ. Anti-CD22-chimeric antigen receptors targeting B cell precursor acute lymphoblastic leukemia. Blood. 2013; 121:1165-1174.