1. Objective(s): This proposal aims to profile abnormal glycosylation in prostate tumors of veterans, to determine if engineered chimeric antigen receptor (CAR) T cells targeting abnormally glycosylated proteins will demonstrate efficacy against bone-metastatic prostate cancer, and to evaluate mechanisms to improve T cell trafficking to tumor sites and enhance resistance to immunosuppression. 2. Research Design: De-identified veteran prostate cancers will be assembled into tumor tissue microarrays and profiled for abnormally glycosylated proteins through immunohistochemical and histopathological techniques, evaluated for spatial N-glycosylated epitopes through MALDI-TOF imaging, and characterized for O-glycosylated through cellular O- glycome reporter and amplification. An animal model of bone-metastatic prostate cancer will be developed through engraftment of a human osteoblast scaffold to support the bone-enrichment of implanted prostate cancer cell lines in NOD-SCID IL2R null (NSG) immunodeficient mice. ? Xenograft animals will be treated with a single intravenous dose of human CAR T cells (n=10 per treatment group) to measure the efficacy and potential treatment limitations of adoptive immunotherapy for bone metastases. Lastly, genetic engineering approaches will be evaluated to improve T cell bone homing and increase resistance to immunosuppression, including ectopic chemokine receptor expression and gene-disruption of immune checkpoint molecules. 3. Findings: Preliminary results demonstrate strong expression of Tn-MUC1 in bone- metastatic prostate cancer. 4. Clinical Relationships: CAR T cells have been explored in the clinic for over 6 years, have demonstrated remarkable success for hematopoietic malignancies, but have lacked sufficient clinical success in solid tumors. Nearly 10,000 veterans are diagnosed with prostate cancer per year and bone-metastatic prostate cancer remains a significant treatment challenge. Successful findings from this study could develop new treatment options for veterans with prostate cancer as well as improve CAR T cell adoptive immunotherapy for solid tumors.
Prostate cancer accounts for nearly one-third of all cancer diagnoses amongst men in the VA patient population, and a percentage of prostate cancer patients will develop bone metastatic cancers, which remain incurable. Best treatment options for bone-metastatic prostate cancer improve overall survival by a modest four months, a strong motivation to evaluate and invest in the development of more efficacious therapies. In the proposed research, we will investigate abnormal carbohydrate expression on the surface of prostate cancers and develop T cell based therapies to target abnormal carbohydrates and glycoproteins in bone-metastatic prostate cancers. We also aim to develop improved methods to deliver T cell therapies to patient tumors and increase the efficacy of such therapies.
|Watanabe, Keisuke; Kuramitsu, Shunichiro; Posey Jr, Avery D et al. (2018) Expanding the Therapeutic Window for CAR T Cell Therapy in Solid Tumors: The Knowns and Unknowns of CAR T Cell Biology. Front Immunol 9:2486|