Cancer is one of the world’s most devastating diseases. One in three women and one of two men will get cancer in their lifetime. How do we defeat it?
Jeff Bluestone, Ph.D., president and CEO of Parker Institute for Cancer Immunotherapy and professor at the University of California, San Francisco, explains how the human immune system can be harnessed to defeat cancer, and how the Parker Institute is accelerating bold research to bring these treatments to more patients.
Read a slightly abridged version of his talk below.
We’ve been fighting cancer for more than 150 years
Medical science has been brutally forceful in its counterattacks on cancer. We’ve cut it out with surgery, poisoned it with chemotherapy, bombarded it with sub-atomic particles through radiation and hit it hard with targeted drugs to block its growth. People are living longer, but these therapies ravage the body; and in the late stages, the cancer almost always comes back.
So, why is cancer so tough to beat?
Cancers look just like normal cells, evading our natural immune system from attack. Mutations cause them to grow out of control, divide and evolve to become drug resistant. To make matters more complicated, cancer isn’t just one disease, but millions. Cancer in one person is different than cancer in another person. Lung cancer is unique to pancreatic cancer or another type of cancer.
The good news is that these are the very problems our immune system is uniquely designed to solve by millions of years of evolution.
The immune system is a finely tuned machine
Through a delicate checks and balances system, the immune system mounts an appropriate response to virus, bacteria, etc., while avoiding autoimmune diseases. Over the last two decades, we have sought to understand this balance, looking for the on- and off-switches that control the fine immunological balance.
It can be likened to the gas and brakes on a car. Too much gas, putting the immune system in overdrive, could lead to an autoimmune disease. Too much brake could shut down our immune system and make us vulnerable to viruses, diseases and cancer.
Cancer shuts off the immune response, but that can be reversed
I will never forget the day my graduate student, Theresa Walunas, walked into my office with an unexpected discovery. She observed that the immune response increased when blocking the binding of a protein called CTLA-4 to its ligand on tissue cells, rather than suppressed. This was opposite to what one would have expected for this molecule at the time. CTLA-4 turned out to be a major off-switch on the immune system — the first one identified, changing the course of my research.
It seemed logical that the brakes that the immune system uses to stop an autoimmune attack would be the same brakes cancer uses to stop an immune response. Many cancers exploit these immune checkpoints by cloaking themselves and actively turning off the immune system preventing it from recognizing and destroying the tumor cells.
In fact, less than two years after our discovery, CTLA-4 blockade was shown to reverse T-cell immune inactivity in animals. Jim Allison, now Professor and Chair of Immunology at The University of Texas MD Anderson Cancer Center and Parker Institute Center Director, and his colleagues showed in mice that blocking CTLA-4 could promote anti-tumor responses.
These efforts, and the discovery of a cousin protein, PD-1, as a second brake on the immune system, led to the development of a new class of anti-cancer drugs called “checkpoint inhibitors.”
The first checkpoint inhibitor to be approved in humans was a CTLA-4 checkpoint inhibitor called ipilimumab. Then shortly thereafter, three PD-1 inhibitors were developed and approved by the FDA.
The development of these checkpoint inhibitors have truly revolutionized cancer treatment over the last decade. The checkpoint inhibitors, both alone, and in combination with each other, have made certain advanced cancers like melanoma and lung cancers curable in a significant number of patients.
Some patients with metastatic tumors that previously would have a prospect of a long-term survival rates of less than 5%, now have over 40% survival rates.
Former President Jimmy Carter, who suffers from metastatic melanoma in his brain and was treated with a checkpoint inhibitor recently said, “I had two weeks to live and here I am building houses with Habitat for Humanity.”
As amazing as these unexpected advances in cancer treatment, immune responses continue to amaze us.
Harnessing tumor-killing T-cells
In 2010, doctors diagnosed five-year-old Emily with acute lymphoblastic leukemia (ALL).
After two rounds and 16 months of chemotherapy, doctors stopped treatment and told her parents, Kari and Tom, they had run out of options. At that point her tumors weighed pounds.
In April 2012, Emily’s parents walked her into the Children’s Hospital of Philadelphia to try one last option. Her parents had enrolled her into an experimental immunotherapy treatment program designed by Dr. Carl June, now a Richard W. Vague Professor in immunotherapy at the University of Pennsylvania and a Parker Institute Center Director. This approach had taken June and his team, and hundreds of other scientists, 25 years to develop.
He suggested something out of a science fiction novel. He wanted to take Emily’s T-cells and use them to synthetically engineer an army of tumor-killing T-cells using an artificial receptor that recognizes a protein on the cancer cells. He then wanted to infuse them back into Emily’s body to seek out and destroy the cancer.
So that’s what he and his team did. They isolated T-cells from Emily’s blood, added the artificial chimeric antigen receptor (CAR), and generated ALL-specific killer CAR T-cells. “Expanded” by 1,000-fold in a tissue culture bag, the cells were injected back into Emily.
At first she became very sick as the CAR T-cells attacked the tumor and spit out massive amounts of the toxic material destined to kill the tumor. But Emily recovered and, like more than 70% of patients, her tumor disappeared.
Six years later, the tumor has not returned. The killer cells are still around to protect against the tumor cells coming back to seek out and destroy them (almost like a vaccination). In the future, we hope to learn how to customize the cells for many different types of cancer including brain, liver and pancreatic cancer.
Emily’s story is now in medical school textbooks, a case study of when just six years ago, this treatment was still considered fringe and unproven.
Not surprisingly, the newest clinical studies are seeking to combine checkpoint inhibitors with genetically engineered T-cells, creating a one-two punch to go after and treat hard-to-reach cancers.
In fact, we are starting our first human trial in the US, where scientists with the Parker Institute are taking T-cells from patients and deleting the PD-1 molecule. This uses a novel approach of gene-editing, CRISPR, which cuts out the gene that produces the checkpoint protein, thus combining the power of checkpoint inhibition with killer T-cell therapy.
Accelerating cancer immunotherapy breakthroughs at the Parker Institute for Cancer Immunotherapy
As a result of his own struggles with allergies and a compromised immune system, Sean Parker, a successful tech entrepreneur, gained a deep understanding of immunology early on. He became convinced that the only path to durable cancer cures would be to engage the immune system.
In 2013, he began work on architecting a new research model to accelerate this research and treatment development revolution. This vision led to the creation of The Parker Institute for Cancer Immunotherapy, which launched in the spring of 2015.
The Parker Institute is designed to remove the biggest non-scientific impediments to breakthroughs—insufficient funding and research resources, and disincentives to collaboration.
Sean has challenged us to take chances, make big bets, take big risks and ask questions too risky for typical funding agencies. If we fail, we fail early and re-deploy resources. We are not constrained by the same rules that govern other industry or government funding.
We have created a sandbox, where there is sharing, trust and confidence, a sense of family, a core group of people, smart and dedicated to the advancement of cures for cancer. Our members are not just scientists, they are collaborators, colleagues and friends, part of a special community.
In short, we want to hack cancer treatment, hack the silo-ized work of academic and industry research and build a better process for doing science and moving discoveries to patients.
Collaborating like never before with the best tools to make bold discoveries
The Parker Institute starts with six of the top cancer research institutes in the country that combine incredible research and clinical assets and a history of translating discoveries into patient care. They are Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, University of California, San Francisco, University of California, Los Angeles, Stanford Medicine and the University of Pennsylvania.
Each center is led by an exceptional cancer immunology researcher committed to pushing the investigative efforts, and engaging many of the best and brightest young cancer scientists, committed to work together to accelerate cutting-edge research.
We have created a shared research agenda that incentivizes high-risk, high-reward science. And these highly innovative projects can bubble up from a single researcher or lab, or they can emerge through our collective “team science” roadmap.
We encourage and facilitate the sharing of inventions, papers, data and insights, well before publication, so that each researcher can benefit from the efforts of all others within the PICI network.
Most importantly, in addition to providing a significant new source of capital for innovative research, we are filling the sandbox with the most innovative technologies and the newest drugs to ensure our researchers are empowered with best-in-class tools and capabilities they need to deliver the boldest discoveries and major research advances.
We are committed to a multidisciplinary effort. As I mentioned earlier, there is an extraordinary convergence in the underlying science and treatment strategies in autoimmune disease and in cancer treatment, but also in medical areas far afield of immunology including nanosciences, metabolism and radiation biology.
Finally, we are partnering with patients. In an age of personalized medicine, every patient is a source of vital information needed to craft effective treatments.
Now is the time
We are in the midst of a genomic revolution that allows us to determine in great detail what the differences are between cancerous cells, even between individual cancer cells. A computational revolution is underway. We have created new ways to collect, manage and analyze the incredibly powerful and almost incomprehensibly large data sets we are gathering.
The Cancer Moonshot, led by Vice President Joe Biden, and leadership in the NCI and the FDA have committed new investments and created new programs to create and test cancer treatment in adults to children with devastating diseases.
And finally, we have extraordinary commitments of philanthropic support to accelerate this research from Sean Parker and The Parker Foundation to Priscilla Chen and Mark Zuckerberg’s Biohub, and Lynne and Marc Benioff’s support of The UCSF Benioff Children’s Hospital and beyond.
The immune system is an intelligent technology platform that is there for us to decode, and ultimately, utilize to beat cancer. Unlike the static, brute force attacks we’ve attempted on cancer in the past, this is a dynamic system that can out-evolve the tumor.
We’re fighting fire with fire to achieve durable remissions. And this is why we will finally succeed where we’ve failed in the past.