Project Title: T-Cell Targeting of Sarcomas
Principal Investigator: Xianzheng Zhou, MD, PhD
, Assistant Professor, Department of
Pediatrics/Medical School, Division of Hematology/Oncology/Blood Marrow Transplantation.
Total RIS funding: $50,000.
Refractory, recurrent or metastatic sarcomas remain as one of the greatest problems in clinic. Administration of insulin-like growth factor-1 receptor (IGF-1R) antibodies to sarcoma patients has demonstrated significant anti-tumor activity. However, many patients develop resistance to the antibodies, and the mortality rate for recurrent sarcoma patients is almost 80-90%. Our hypothesis is that genetically engineered T cells which now express a chimeric receptor that selectively binds to IGF-1R can specifically target sarcomas, including drug- or antibody-resistant sarcomas.
To test our hypothesis, we will employ the Sleeping Beauty transposon system, a piece of naked DNA, to insert a dual gene containing the chimeric receptor for IGF-1Rand a tag/suicide gene into the T-cell genome. The chimeric receptor instructs T cells to selectively bind to and kill the target, while a tag/suicide can be used to enrich gene-modified cells and also to eliminate them in vivo if an adverse effect were to occur. T cells from sarcoma patients and healthy blood donors (as control) will be engineered with the Sleeping Beauty, selected for expression of a tag gene, and then evaluated for their cytotoxic functions and target specificity against a panel of sarcoma cell lines. Our research will quickly lead to the development of a novel cell therapy for the treatment of a broad range of sarcomas including Ewing, rhabomyosarcoma, and osteosarcoma along with other types of solid tumor (breast, prostate, lung, colon, thyroid, renal, adrenal cancer, and retinoblastoma) and hematological malignancies (multiple myeloma, lymphoma and leukemia).
Name(s) of project collaborator(s)
- Doug Yee, MD, Professor, Department of Medicine/Medical School, Director of Masonic Cancer Center. Providing IGF-1R scFV eDNA.
- Deepali Sachdev, PhD, Assistant Professor, Department of Medicine/Medical School. Providing IGF-1R scFV eDNA.
- Daniel A. Mulrooney, M.D., M.S., FACP, Assistant Professor, Department of Pediatrics/Medical School, Division of Hematology/Oncology/Blood and Marrow Transplantation. Obtaining sarcoma patient's peripheral blood and helping moving this work into a Phase I clinical trial.
- Brenda J. Weigel, M.D., M.S., Associate Professor, Department of Pediatrics/Medical School, Division of Hematology/Oncology/Blood and Marrow Transplantation. Obtaining sarcoma patient's peripheral blood and helping moving this work into a Phase I clinical trial.