Long-Acting PEG-Like Conjugates of an Immune Checkpoint Inhibitor and a Selective Cytokine for Combination Immunotherapy
Abstract
My career goal is to become a world-class independent cancer researcher and a tenure-track faculty member in a biomedical engineering department at a top-tier academic institution. The Horizon Award will advance my career by allowing me to gain a multifaceted skill set and ensure my intellectual independence to position me to tackle a wide range of biomedical problems in my future career as an independent investigator. This goal will be achieved through a customized and comprehensive researcher development plan that starts with a new design to create innovative drugs and ends with benchmarking of the developed drugs to the ones presently used in the clinic. These experiences will enable me to eventually run a lab that bridges the current translational gap in cancer therapy by developing innovative interventions to cancer. My short-term objective is to develop better and safer cancer drugs than the ones that are presently used in the clinic. This research project is motivated by the fact that not all cancers are responsive to a revolutionary cancer treatment—immunotherapy—that uses a class of drugs called immune checkpoint inhibitors. This is mostly because of insufficient infiltration of immune cells into the tumor to exert their activity and insufficient activation of the immune system to recognize and destroy tumor cells. Anti-tumor effects may be also limited by the low tumor penetration of this class of drugs due to their large size and structural inflexibility, preventing them from effectively penetrating into tumors. To further activate the immune system, another class of drugs—cytokines—are used. Unfortunately, cytokines result in life-threatening side-effects and ambiguous clinical activity due to their lack of selectivity. Even if these problems are solved, cytokines are eliminated from the body shortly after administration via the kidneys, preventing them from exerting their anti-cancer effect. PEGylation—attachment of polyethylene glycol—is the most commonly used method to improve the blood circulation time of cytokines, but it causes severe allergic reactions in some patients and abrogates clinical effectiveness of the drugs. These reactions have led to the withdrawal of several drugs from the market and termination of the clinical trial of a drug candidate. These problems have been traced to pre-existing molecules—PEG antibodies—that are found in approximately 50% of Americans and even in individuals who have not previously received a PEGylated drug, possibly due to the presence of PEG in many consumer products. Hence, there is an unmet need for a therapy that overcomes these problems while effectively treating cancer. I hypothesize that I can develop a therapy that overcomes these problems and treats colorectal and pancreatic cancer in a much more efficient way than the drug currently used in clinic—atezolizumab—and chemotherapy alone, respectively. In preliminary studies, I have developed a platform that extends the blood circulation time of drugs without showing any interaction with PEG antibodies in addition to a new, modular drug that hits the same target with atezolizumab. I propose to combine this next-gen PEGylation technology with this new drug and a selective cytokine to develop a new immunotherapy for cancer treatment. My long-term objective is to use this platform to generate new drugs and delivery technologies that can treat a broad range of cancers that afflict Americans. The platform developed in this research has the potential to alter the landscape of the drugs used in cancer therapy, as it allows fast development (approximately 1 year) of better and safer drugs and combines them with a new delivery technology for cancer treatment. Given that over 1.7 million Americans are diagnosed with cancer every year, ~3% of whom are Veterans, it has the potential to have a broad impact in medicine and cancer survival of active duty Service members and Veterans.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010671
Entities
People
- Imran Ozer
Organizations
- Duke University
- United States Army