Cancer Immunotherapy: Living Up to the Promise
Much like last year, we expect a lot of discussion and new data on cancer immunotherapies to be presented at the 2014 American Society of Clinical Oncology (ASCO) Annual meeting. The immunotherapy field is evolving fast and is one of today’s most promising approaches to treating cancer.
This class of medicines is designed to harness our immune system’s ability to adapt, evolve and remember as the disease evolves. The immune system is powerful, and the goal of immunotherapies is a long lasting response to treatment.
Every day, we are learning more and following nature’s clues. Here are a few things we're thinking about at Genentech.
DECODING CELLULAR CAMOUFLAGE
Cancer cells use what we call "cellular camouflage" to fool the immune system into thinking they are normal cells. There are many conceivable ways to stop this farce. And today, there are more than 20 potential cancer immunotherapy targets under active investigation in the laboratory and clinic attempting to do just that.
Each type of cancer is likely to elicit a different type of immune response. For example, it’s well understood that kidney cancer can respond to medicines that modify the body’s immune response. In our labs, we’re following these types of hints to broaden the potential uses for immunotherapies.
Today, we know the relationship between cancer and the immune system is very complex. Cancer cells can disguise themselves and stop the immune system from attacking. The immune system also may not be able to mount a strong enough attack in the first place.
For some kinds of cancer, we will likely have to do several things simultaneously to overcome cancer’s tricks: see past the camouflage, release the brakes and push the gas. One of the trickiest things about cancer is that it often exploits our own self-protective maneuvers to protect itself. We have to be careful not to remove all the normal checks on immune activity, as this could cause the immune system to attack our bodies.
For a basic understanding of the complexity behind this balance, take our immunotherapy challenge (below). Please note that this module is optimized for desktops and tablets. The experience will be slightly degraded on phones.
SMARTER BY DESIGN
Immunotherapy as a class of medicines may include small molecules and cell-based therapies as well as therapeutic antibodies. Designing antibody-based immunotherapies illustrates unique challenges related to stimulating an immune response while avoiding potentially harmful immune activity. It's an interesting puzzle, and what we call the antibody-dependent cell-mediated cytotoxicity (ADCC) paradox.
ADCC is a technical way of describing how antibody-based medicines bind to their target cancer cells and recruit the immune system to destroy those cells. Some therapeutic antibodies for cancer are specifically engineered to have increased ADCC activity, with the goal of amplifying immune activity against the cancer.
This is a reasonable approach for targets that are only found on cancer cells. But what about targets that may be present on normal immune cells, if only in very tiny amounts? In those cases, the action of the therapeutic antibody could cause the immune system to turn on itself.
To avoid this, we have engineered some of our immunotherapy antibodies in the opposite way – to potentially decrease their ability to kill cancer cells through ADCC.
Engineered antibodies and antibody-cytokine conjugates can be designed to act as “beacons” to flag a tumor for destruction by the immune system.
One theory about immunotherapies is that they could work for everyone, with any type of cancer. The data to date show that this isn’t the case. Even though everyone has an immune system, not all patients will respond to the same medicine in the same way.
Our immunotherapy program at Genentech has a large biomarker and diagnostic focus so we can find those who are most likely to experience a meaningful benefit.
But what about those who do respond, but not well enough?
Perhaps those people with a small to moderate response should be candidates for combination trials. Some immunotherapies may be more effective if they are combined with different types of medicines, including chemotherapies, personalized medicines and even other immunotherapies.
In this way, biomarkers for cancer immunotherapy don’t just tell us who will or will not respond. Rather, they could help guide treatment strategies involving one or more medicines.
We should look to biomarkers for immunotherapy to help us find who is eligible for combination trials, rather than who is or is not eligible for a single medicine.
LEARNING FROM THE PAST
There is a lot of excitement about cancer immunotherapies – and there should be. But we have to be cautiously optimistic – a single new class of medicine is unlikely to be a panacea for all cancers.
In some ways, this is similar to the situation with targeting tumor angiogenesis. Nearly 15 years after the first data on our angiogenesis program was presented at ASCO, we are still learning where and how these medicines should and could be used. We must approach immunotherapies in the same way – with relentless scientific rigor.
At the same time, the pace of scientific learning is advancing faster than ever, and we can now personalize treatment approaches from the very beginning of clinical development. We can begin combination trials and forge unique pathways to regulatory approval much earlier.
By following nature’s hints, we may be closer than ever to realizing William Coley’s vision for immunotherapy. To do this, we must build on our knowledge, apply the right tools and ask the right questions.
Start today by thinking differently about immunotherapies:
Daniel S. Chen, MD, PhD, is Global Development Team Leader for Anti-PDL1 at Genentech/Roche, Group Director in Product Development Oncology and Adjunct Faculty in Medical Oncology at Stanford University. He received a BS degree in Biology from the Massachusetts Institute of Technology (1990), a PhD in Microbiology & Immunology (1996) and MD (1998) from the University of Southern California.
Daniel completed an Internal Medicine Residency and Medical Oncology Fellowship at Stanford University (2003). He went on to complete a Post-doctoral fellowship with Mark Davis in Immunology, where he was a Howard Hughes Medical Institute Associate. He also ran the metastatic melanoma clinic at the Stanford Cancer Center from 2003-2006, where he continues to care for melanoma patients. In that time, he studied human anti-cancer immune responses pre- and post- cancer vaccination and cytokine administration to determine why anti-tumor immune responses were not more clinically effective. He received a U19 grant to develop better immunologic tools to interrogate human immune responses and ultimately patented the MHC cellular microarray to detect and functionally characterize antigen-specific T cell states.
Since joining Genentech in 2006, Daniel has focused on the clinical development of anti-angiogenic and immune modulatory targeted therapies in both early and late development, as well as the diagnostic tools to aid their development. He is a reviewer for Clinical Cancer Research, has been an invited speaker at the AACR Annual Meeting 2014. He has continued to publish with academic and Genentech collaborators in the field of cancer immunotherapy.