Development of Precision Immunotherapy for Advanced Prostate Cancer
Abstract
A major problem faced by medicine in the treatment of prostate cancer is that the diseased cells can become unrecognizable to the white blood cells that normally combat abnormalities. Physicians are trying to get around this problem by "programming" cancer-fighting lymphocytes to recognize molecules on the surfaces of cancer cells that make them distinctive from normal cells. Currently, the usual approach is to isolate the lymphocytes from the blood of cancer patients, "teach" them to recognize cancer molecules using elaborate genetic programming procedures, and then grow them into numbers high enough to have an effect when they are returned into the bloodstream of the patient months later. Unfortunately, like all cancers, prostate tumor cells display a spectrum of molecular properties; in fact, it is this diversity that enables them to evade natural immune responses. Our approach involves the creation of "chimeric antigen receptors," which are cell surface proteins that are able to recognize and bind to particular macromolecules called antigens on the surface of the cancer cells. When the patient s lymphocytes are programmed to produce these receptors, they cause the destruction of cancer cells bearing the relevant antigen, but of course, those cancer cells that don t carry the antigen are not affected. We therefore program, at the same time, lymphocytes that make receptors to two additional kinds of antigens. We expect that, in combination, these programmed lymphocytes will eliminate all, or nearly all, cancer cells. The second aspect of our project is to use microscopic spheres called nanoparticles to carry the DNA required to produce the chimeric antigen into the lymphocytes as they circulate in the bloodstream rather than isolating them from the patient. This simplifies the procedure radically and produces a much faster response: binding of the lymphocyte to a cancer cell not only results in destruction of the tumor, but stimulates the lymphocytes to proliferate, too. The nanoparticle reagents are easily manufactured in large amounts and are stable, so they can be stored for a long time. Thus, it is easy to envision the ability of a physician to quickly select and administer an off-the-shelf reagent that specifically matches the molecular properties of the patient s tumor. Finally, administration of the reagent involves simple infusion that can be accomplished in an outpatient setting. If we find there are still prostate cancer tumors that evade attack by the lymphocytes programmed to make the three antigen receptors we plan to initially study, we will take a close look at their genes to see what other kinds of antigens they are making so we can create lymphocytes with chimeric receptors for them, too. Thus, by the end of the project, we will know the best way to program lymphocytes to make sure all of the prostate cancer cells are eliminated. Thus, our project addresses major challenges faced in treating cancer. Immune-based therapy represents an important new dimension for fighting cancer because traditional treatments have centered on DNA-damaging interventions and interruption of important cellular programs -- both of which have very negative side effects. Our goal is to evaluate the effectiveness of precision immunotherapeutics that specifically target a selected spectrum of prostate cancer subtypes. We can implement them using a novel bioengineering approach that modifies lymphocytes while they are still in the patient. We will furthermore identify mechanisms of resistance to immune-based therapies, so even more effective agents can be developed.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510563
Entities
People
- Matthias Stephan
Organizations
- Fred Hutchinson Cancer Center
- United States Army