Personalized T-Cell Immunotherapy for Renal Cell Carcinoma
Abstract
Kidney cancer is the eighth most common malignancy in the United States and ~14,400 patients are estimated to die of this disease in 2017. Risk factors for kidney cancer include hypertension, obesity, diabetes, smoking, and exposure to certain chemical compounds; these risk factors are prevalent in active duty and military Veteran populations and the American public. While early stage kidney cancers are potentially surgically curable, advanced stage and metastatic disease (~30% of cases) carry a dismal prognosis. Current mainstay targeted therapies for advanced kidney cancer (e.g., VEGFA and mTORC1 inhibitors) are palliative at best with only a short improvement in patient survival. On the other hand, the most common type of kidney cancer is potentially susceptible to complete eradication by the immune system. Patients treated with modern therapeutics that boost immune activity (e.g., anti-PD1 and anti-CTLA-4 antibodies) occasionally show long-term reduction and control of tumor burden. Cutting-edge therapies with custom engineered immune cells (T cells) have recently been shown to eliminate some leukemias and lymphomas, and adopting a similar strategy is of great interest for patients with advanced stage kidney cancer to boost treatment response, reduce side effects, and potentially achieve cures. However, efficient testing of the numerous and increasing combinations of targeted- and immuno-therapeutics with engineered T cell therapies before administering them to patients in a reasonable timeframe has proven difficult. This is because the currently used testing platforms are too simplistic/artifact-prone (e.g., tumor cells grown by themselves in flat layers on a dish without blood vessels or other tumor components) or expensive, slow, laborious, and not fully humanized (e.g., animal models with engrafted human tumors). To solve this problem, the initiating PI (Akilesh) and collaborators have recently developed a kidney-cancer-on-a-chip -- a miniaturized version of kidney tumors, complete with blood vessels, that are grown in a three-dimensional matrix within a sterile plastic chip device in the laboratory. Tumor growth and blood vessel formation are readily visualized in these devices and can be manipulated with drugs or, potentially, immune cells. In parallel, the partnering PI (Tykodi) is an established clinician-investigator with particular expertise in emerging engineered T cell immunotherapies for kidney cancer. With our combined resources and expertise, and armed with preliminary data, demonstrating feasibility, we propose to further develop the kidney-cancer-on-a-chip into a mature preclinical platform for testing of engineered T cell therapies. A patient-specific vascularized tumor-on-a-chip immunotherapy platform does not presently exist for kidney tumors or any other cancer. Successful completion of our experiments would therefore accelerate preclinical testing of modern immune-based therapies while simultaneously providing a physiologically relevant system for experimental studies in the laboratory. This will enable bidirectional translation of research findings between the clinic and the laboratory. While our system overcomes shortcomings of current preclinical testing strategies, it still does not fully capture the full complexity and heterogeneity of tumors in patients. However, since the devices are fully customizable, additional tumor components can be added in the future to improve complexity and better imitate the tumor within the laboratory environment. While our findings will apply directly to kidney cancer, it is anticipated that the knowledge gained in these studies could be broadly applicable to animal-free studies of immunotherapies for other cancer types. Since our chip devices will incorporate the patients own tumor and blood vessel cells with his/her own engineered immune cells, with further development they could serve as a rapid readout (~1-7 days) for that patients r
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910789
Entities
People
- Scott Tykodi
Organizations
- Fred Hutchinson Cancer Center
- United States Army