A Breakthrough Treatment with Broad Implications
As the representative inventor on one of the six cancer immunotherapy treatments being honored for the 2016 IPO Education Foundation’s Inventor of the Year Award, Yan Wu of Genentech and her team are helping to clear a path toward more effective cancer management. Dr. Wu helped to identify the antibody that would serve as the basis for TECENTRIQ, a monoclonal antibody designed to bind with programmed death-ligand 1 (PD-L1), a protein implicated in the suppression of the immune system. TECENTRIQ is the first anti-PD-L1 cancer immunotherapy approved by the U.S. Food and Drug Administration (FDA)—it was granted accelerated approval in May 2016 for the treatment of people with a type of bladder cancer called urothelial carcinoma whose cancer has spread or cannot be treated by surgery, or who have tried chemotherapy that contains platinum and it did not work or is no longer working. In October, it was granted FDA approval for the treatment of certain types of patients with metastatic non-small cell lung cancer (NSCLC), and more clinical trials are in the works for other applications.
Dr. Wu came to the United States from China and obtained her Ph.D. in Molecular Cellular and Developmental Biology from the University of Colorado at Boulder in 1995. She joined Genentech in December 1996 as a postdoctoral fellow in the Department of Molecular Oncology and today is Director and Principal Scientist in Genentech’s Department of Antibody Engineering. Her initial work with the company was in cancer signaling pathways, but about 15 years ago she switched her focus to therapeutic antibody discoveries, in part, she says, “to be closer to our pipeline and to work on more directly helping patients. That’s my goal.”
Dr. Wu spoke with Innovator Insights about how TECENTRIQ works, why it represents a new era in cancer treatment, and what the future holds for this transformative area of research.
Can you describe the process of developing TECENTRIQ?
My work on TECENTRIQ really started, when a scientist in the Immunology Department came to me to propose an antibody discovery project targeting PD-L1, a protein implicated in the suppression of the immune system, to activate T Cells (a type of lymphocyte, or white blood cell, that helps to fight threats to the immune system). My lab generated the lead, or the blocking antibody, in close collaboration with research colleagues at Genentech. Using phage display technology, we generated and optimized an antibody via “affinity maturation”—a process for achieving higher affinity antibodies—and ultimately got an antibody ready to be the clinical candidate. We got the sequence of the parental clone four days before Christmas, which was very exciting.
How does TECENTRIQ work?
In the simplest terms, TECENTRIQ turns the immune system back on so it can eradicate the cancer cells. To go into a little bit more detail, our immune system has a type of cells called lymphocytes, or T Cells, which can help the body to fight off disease, such as infections and cancers. However, cancer cells can express a protein called PD-L1, and this protein can bind to its receptor, PD-1, on the T Cells and inactivate T Cell signaling. TECENTRIQ is a monoclonal antibody; it binds specifically to PD-L1 and blocks the interaction between the ligand and the receptor – PD-L1 and PD-1—thereby reinvigorating the activated T Cells and helping to fight the cancer cells.
We’re not just looking for incremental changes—we’re looking for the next “big one.”
How is it—and immunotherapy in general—different from previous treatments?
Cancer immunotherapy is so groundbreaking, and that really comes from the clinical data for the last five years. It’s really a transformative approach to treating a variety of cancers that we have not been able to treat before. There are three major aspects to its transformative nature. First, the clinical benefits are really unprecedented. They can achieve long-term survival and remission in patients for whom previous therapies have not worked, which is very exciting. Second, patients tolerate these therapies very well—in many cases, we do not see the nasty side effects that exist with the traditional therapies like Chemo. And third, there is broad applicability for these treatments. It’s really amazing that one therapy can be used to respond to a variety of cancers, whether on its own or in combination with other cancer therapies. That’s really unprecedented, that one drug can be effective against so many diverse cancer types.
Is there such broad applicability for TECENTRIQ as well?
It was first approved for bladder cancer, now for lung, and there are many more clinical trials in process to potentially treat other types of cancers, so this is hopefully just the beginning.
TECENTRIQ has a huge, bright future. It represents a whole new approach to treating cancer by resetting the immune system. I’ve been working in the cancer treatment field for many years and for the last five years cancer immunotherapy has changed the whole paradigm of cancer biology and oncology therapy. This is driven not just by hype, but actual clinical responses—particularly the durability data. In the future, it’s really setting a high bar for new therapies that might come along the way, which is great news for patients.
What role have patents played in your career?
Especially for my job, because we are generating the clinical candidates, patents play a really critical role in my work and for industry in general. For industry, patents are a lifeline to support the innovative work we’re doing. Of course, the ultimate goal is to bring breakthrough medicines to patients. Patents support the innovative work and also support us as individual inventors; to have an issued patent is really a great recognition of our work. I can personally attest to that—while at Genentech I’ve received over 50 issued patents and many more patent publications; it’s a way to recognize the work that colleagues and I have done trying to help patients.
Did you learn about the importance of patents during your academic training?
In the next 10 years the more realistic goal is to say we hopefully can look forward to cancer becoming a more manageable chronic disease, like other chronic diseases, rather than a leading cause of death.
In my work as a Ph.D. I didn’t really learn anything about patents. I learned by working at Genentech for the last 20 years. We have a lot of training, especially for my job. We have official training provided by patent attorneys and I also learn just on a daily basis. I work very closely with all the patent attorneys here and we have a very strong patent department; all the patent attorneys have advanced degrees in science with most being Ph.D.s, so in a way we speak the same language. We work closely in drafting the patents and deciding together when and how and for what to file the patent, which is really critical to the success of the company and industry. It’s one of my main duties.
What does the next decade hold for cancer treatment?
I think for all of us working in this field, our ultimate goal we hope is to cure cancer; but for the next 10 years the more realistic goal is to say we hopefully can look forward to cancer becoming a more manageable chronic disease, like other chronic diseases, rather than a leading cause of death. Of course, we still have a long way to go and need to do a lot of work. TECENTRIQ and other immunotherapies are still only effective for a small percentage of patients. To achieve the maximum benefits, we really need to increase the percentage of responders.
At Genentech, we’re using a variety of approaches to generate the next transformative medicine, and we believe it’s possible with what we’ve seen with the current immunotherapies. We’re not just looking for incremental changes—we’re looking for the next “big one.” We’re also looking more now at the overall survival of the patient, not just progression-free survival. We’re doing two new things to further improve the benefit of immunotherapy, such as TECENTRIQ. The first thing is we’re looking at combinations. For example, TECENTRIQ works by taking the brakes off of T Cell activation, so we’re looking for other therapies that could further activate the T Cells. That’s one example of a possible combination. We’re actively working on those kinds of possibilities.
Secondly, we’re actively working on personalized cancer therapies. By looking at each patient’s immuno profiles we can decide the best approach for that individual patient. For example, in each patient, the cancer has different mutations; so one thing we just started working on is personalized vaccines for cancer therapies. We’re looking for the specific mutations in each patient and using our knowledge of human genomics and T Cell biology to identify the neo epitope for that patient—essentially, a personalized vaccine. Hopefully we can design medicines that are geared to individual patients, because no one medicine will work for every patient. The whole field is very exciting, but we have a lot to do.
What does the Inventor of the Year Award mean to you?
It is really the dream to see the work we did in our lab go from bench side to bedside.
I’m really honored. For me, as someone doing early research for drug discovery it is really the dream to see the work we did in our lab go from bench side to bedside—very few of us get the chance to see that, so I feel extremely grateful to work in such a great company and to have this opportunity to see something I worked on truly helping patients. Being able to accept this award on behalf of Genentech is a huge honor in my career.
The other drugs being honored are also wonderful. Our industry is working together to tackle cancer; we should continue to work together to achieve the “next big thing.”