Can our immune system be taught new tricks? Dr. Ron Levy, M.D. is a professor of Medicine and Chief of the Division of Oncology at Stanford University School of Medicine. He specializes in lymphoma and his work has led to the concept that antibodies can be used as personalized anticancer drugs and to the development of an antibody-based drug, Rituxan, that is widely used to treat lymphoma. Café Sci’s very own Byron Brown whose life was saved and extended thanks to Rituxan had the honor of introducing Dr. Ron Levy as the latest speaker in this series.
Levy believes that treatments have to be practical, affordable, and available to really make a difference in the world.
How the immune system works
There are billions of B-cells and T-cells in your blood that each have a receptor on its surface to recognize foreign objects such as bacteria and viruses. These cells circulate throughout the body patrolling for infections and then reject them. Cancer on the other hand is not a foreign invader, but the body’s own cell that decided to go haywire and replicate itself. Therefore, it slips through the cracks of our immune system. When Levy began his laboratory over 40 years ago at Stanford University, his goal was to use the immune system’s antibodies to fight not only invaders from the outside but also invaders from the inside.
Immortalizing antibodies through hybridization
Cancer cells have a property that prevents them from dying naturally making them immortal. Scientists were able to create antibodies with the same property by fusing an immune cell together with a cancer cell through hybridoma technology. The cells are then cloned one at a time leading to billions of cells with antibodies that live forever. Levy and his team were able to develop a monoclonal antibody treatment from hybridoma technology that targets tumor cells of leukemia and lymphoma patients. However, the treatment needed to be customized to each patient making it expensive and time consuming. The first of many successfully treated patients was Phillip Karr who showed massive shrinkage in his lymph nodes within a month of treatment. He was able to live an additional 30+ years after being treated.
Rituxan in the making
Publishing the results gave way to the rise of the antibodies biotech industry. IDEC Pharmaceuticals, a company started by Levy and others, continued to develop this idea of a boutique treatment for each patient. It was decided soon after that creating a treatment unique for each patient was unsustainable. Instead, an antibody drug that was good for everyone became desirable. IDEC developed an antibody with a different target from the original treatment. It targeted what scientists call CD-20 which is found in normal B-cells. Levy was concerned that it would take away all of the special features of the target they were going after, but the company moved forward with the drug and called it Rituxan. However, Rituxan proved to have no adverse effects and about half the patients went into remission after using it. It was later discovered that Rituxan also positively affected autoimmune diseases like multiple sclerosis and rheumatoid arthritis. Levy has since retracted his initial concerns and now recognizes that it was actually a good idea. An important lesson he learned is that in order to really change the world, a new treatment has to be practical, cost-effective, and made available.
Paradigm shift in oncology
There has been a recent shift in focus from targeting tumor cells directly and killing them to now targeting immune cells in a way that re-educates the immune system. That way the immune system knows to go after the cancer cells itself. This realization was made by Dr. James Allison during his time at University of California Berkeley. He made a monoclonal antibody that takes the breaks off the immune system which allows the T-cells to go wild and attack cancer cells. However, if the wrong T-cells go wild then they could end up attacking other parts of the body. The risks and benefits of doing this were high. Around the same time, Dr. Tasuku Honjo, M.D. of Japan cloned a gene called PD-1 that is another property of the immune T-cell. PD-1 receives a signal from cancer cells telling it to not kill them even if the immune cell detects them. Honjo and other scientists were able to create a monoclonal antibody called PD-01 or anti PD-1 which turns off the signal received by PD-1 allowing immune cells to kill cancer cells. Since everyone has an immune system, this antibody is effective on patients with varying types of cancers such as skin, lung, bladder, and many others. Both discoveries earned Allison and Honjo the Nobel Prize in Physiology and Medicine in 2018.
We have progressed from targeting the immune system against targets we know to now communicating with the immune system and taking the breaks off so that it can find its own targets. Lowering side effects and avoiding toxicity within patients is Levy and his team’s current goal. They are now trying to treat cancer with an injection of an antibody combination directly into the tumor. It takes the breaks off only in the area of the immune cells oriented around the cancer cells. This reduces the side effects by keeping the breaks on for the other immune cells in the body. After the immune cells influenced by the antibody has killed the cancer cells at the site of injection, they can begin patrolling the rest of the body looking for cancer cells that may develop later on. Therefore, stopping cancer in its tracks in the form of vaccination. Clinical trials are being held at Stanford University to test this new idea.
In case you missed this exciting talk, watch the video recording here.