Pilot Development of New Forms of Chimeric Antigen Receptor Therapies for Kidney Cancer
Abstract
Rationale and Scientific Objective: Kidney cancer at its late stage is highly lethal, currently with little success in treatments, where the distant type has a 5-year survival rate of only 12%. Recently, immunotherapy has shown success in treating kidney cancer, however, the majority of patients still do not benefit from it. There is an unmet medical need in kidney cancer that calls for innovative and potentially better treatments. Cell therapies such as chimeric antigen receptor T cells (CAR-Ts) have been proven to be powerful cancer therapeutics. CAR-T cell adoptive transfer therapy has demonstrated remarkable efficacy in the treatment of hematological cancers and is approved by the Food and Drug Administration (FDA). However, despite its current success, there remain major challenges for CAR-T therapy. No CAR-T therapy has been approved by the FDA for solid tumors so far, including kidney cancer. Thus, engineering better CAR-Ts is critical to allow CAR-Ts to achieve their full potential against solid tumors such as kidney cancer. Therefore, the objective of this project is to harness our enabling technologies to generate, test, and further develop new forms of potentially better CAR-T therapies against kidney cancers. Addressing FY20 KCRP Areas of Emphasis: (1) Therapeutic Development and (2) Genetics The Ultimate Applicability of the Research: This project, if successful, will establish new forms of promising cell therapy candidates with enhanced antitumor efficacy against kidney cancer. The success of this project will enable us to advance the best version into translational activities and early phase clinical trials. This, if it continues to succeed, can provide brand-new and promising CAR-T cell therapies for the treatment of kidney cancer patients. Virtually all types of kidney cancer patients with the surface antigen expressed can in principle be targeted by specific CAR-T cell treatments, in line with the emerging regimen of targeting the molecular nature of cancer rather than pathology alone. This is especially useful for those patients at the late stage of the disease, who are often out of options. Although clinical trials are outside the scope of this project, its short-term success can have an important outcome that will bridge the gap of early development to lead candidates, making it ready for the next stage of translation, i.e., investigational new drug-enabling activities. Besides our own cell therapy leads, the longer-term impact of this proposed research project also includes providing a number of powerful technologies for the field of kidney cancer so that many more promising cell therapy candidates can be rapidly developed in the future to benefit kidney cancer patients across Service Members, their families, Veterans, and the American public. The innovative aspects of the proposed research project: One of the most efficient ways to engineer better persistent CAR-T is to engineer thousands of different CAR-T variants and efficiently select the best ones. We have built a novel system that enables stable CAR-T generation at high efficiency in one step. The modularity of our system enables flexible and efficient generation of multiple CAR elements in the same T cell. We recently developed a second and more advanced system, which is a novel and highly enabling platform for advanced massively parallel CAR-T engineering. These versatile systems open new capabilities of therapeutic cellular engineering with simplicity and precision. They also allow us to achieve massively parallel engineering of CAR-Ts and identify the best candidates for potential therapeutic applications by exhausting many possible candidates and thereby providing lead therapies with enhanced efficacy or other desirable features against kidney cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110514
Entities
People
- Sidi Chen
Organizations
- United States Army
- Yale University