Small Molecule Drugs to Improve CAR T Therapy
Screening for compounds that promote expression of CAR T targets
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 now focuses on immunotherapy for pediatric cancers. 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 microenvironment around tumors.
The Orentas lab and collaborators developed CAR T cells that target CD22, a cell-surface protein on B-cell acute lymphoblastic leukemia (B-ALL) cells. The CD22-targeting CAR T cells expand in patients with B-ALL and have anti-leukemic activity. However, patients can experience relapse or recurrence if the leukemia cells downregulate CD22 expression. Small molecules such as bryostatin are known to prevent the decrease in CD22 expression.
Dr. Orentas is interested in partnerships to screen libraries of small molecule drug candidates for their potential to promote CD22 expression on leukemia cells. Candidate compounds might alter CD22 gene expression through epigenetic modification, for example. The Orentas group has expertise and resources for small molecule screening such as leukemia cell lines and primary cells from B-ALL patients. The Orentas lab has experience and facilities for using mouse cancer models to test if candidate drugs extend and enhance CAR T effectiveness against leukemia in vivo.
Dr. Orentas serves as both the Director of the Ben Towne Center for Childhood Cancer Research and as 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 creating a new generation of CAR T cells through innovative pharmacologic and synthetic biology approaches..
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
- 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): 7088-7095.
- 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.
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