The Emergence of Philanthropy to Fund High-Risk, High-Reward Cancer Research

A Conversation With Jeffrey Bluestone, PhD




The greatest challenge to individual scientists today is bringing together all the resources necessary to address the most challenging questions in immunotherapy. We are committed to reducing the barriers and helping researchers work together in a more efficient, seamless way.
— Jeffrey Bluestone, PhD

Earlier this year, Sean Parker, the cofounder of the music streaming service Napster and an early president of Facebook, joined a growing list of entrepreneurs who are committing large portions of their wealth to funding cancer research. In April, Mr. Parker announced he was donating $250 million to launch the Parker Institute for Cancer Immunotherapy, a multi-institutional endeavor to accelerate the development of breakthrough immunotherapies with the potential to cure more cancers. The six academic institutions involved in the Parker Institute include Memorial Sloan Kettering Cancer Center, the University of Pennsylvania, The University of Texas MD Anderson Cancer Center, Stanford Medicine, and the University of California campuses in San Francisco (UCSF) and Los Angeles (UCLA). First-year funding for each center is between $10 million and $15 million.

The Institute, which is bringing together the work of about 350 researchers in 50 laboratories on the 6 academic campuses, is initially focusing on 3 key areas of immunotherapy research:

  • Developing novel approaches to modify T cells, to enhance their function and find the next generation of more effective T-cell therapies
  • Investigating reasons many patients with cancer do not respond to checkpoint blockade agents, such as anti–PD-1 (programmed cell death protein 1) and anti–CTLA-4 (cytotoxic T-lymphocyte–associated protein 4), or relapse after receiving them, and testing novel pathways and treatments to improve the rates of durable responses and broaden the use of these agents in novel combinations to treat more types of cancer
  • Advancing RNA sequencing, antigenic peptide discovery, and immune monitoring technologies to identify novel individual and shared tumor antigen targets to understand how to develop new vaccines and T-cell therapies to target tumors more effectively.

Subsidizing Federal Funding

Although there is no comprehensive tracking of the magnitude—or impact—of science philanthropy, a 2012 analysis by the National Bureau of Economic Research put the combined donations from both individuals and private foundations at over $4 billion annually,1 a figure that pales in comparison to the $60 billion in scientific grants made by the federal government each year.2 Still, while not a replacement for public dollars, private donations can fuel the kind of scientific innovation that is often not possible in more traditionally risk-averse government grants.

“Sean [Parker] is very cognizant of the funding challenges that have existed in the scientific community, as funding from the National Institutes of Health has remained flat or been reduced in real spending power. There is a need for others to step up and make up some of that funding loss at a time when the most exciting opportunities are happening in biomedical research that can change people’s lives,” said Jeffrey Bluestone, PhD, President and CEO of the Parker Institute for Cancer Immunotherapy and A.W. and Mary Margaret Clausen Distinguished Professor at UCSF. 

“He is also aware that with the shortage of federal funding and the challenging circumstances that have been in place for the average researcher, the system has become a little broken,” Dr. Bluestone continued. “By creating a new kind of environment for doing research with different rules and enough resources to make big bets and try risky projects, Sean is hoping to change the dynamic of what it means to investigate a hard problem, put energy into it, and not have research be diluted by a lot of different focuses, but instead target this one particular area of cancer research, immunotherapy.”

Over the past 25 years, Dr. ­Bluestone has focused his research on understanding the basic processes that control T-cell activation. In 1996, he and another investigator, James P. ­Allison, PhD, Chair in the Department of Immunology and Executive Director of the Immunotherapy Platform at MD Anderson Cancer Center, identified CTLA-4 as an inhibitory checkpoint molecule, which restricted activated T-cell ­responses. 

The ASCO Post talked with Dr. ­Bluestone about the goals of the Parker Institute for Cancer Immunotherapy, how the partnership among the six academic institutions will spur innovative cancer research in immunotherapy, and the prospects of curing cancer.

Consortium Mission

What is the mission for the consortium of six academic centers in the Parker Institute for Cancer Immunotherapy, and how are they coordinating their work?

We have set up two approaches to facilitate scientific discovery. One was to give each of the centers $10 million to $15 million in the first year to develop projects—early-stage cutting-edge, independent projects, including early-phase clinical trials—within its own institution or in collaboration with other institution investigators and share progress and data throughout the network. Progress in the individual projects is mapped against the global strategic effort we all agreed to, allowing the Institute to provide, where possible, additional resources to move the most promising efforts forward. There are currently 15 to 20 projects that have been launched to reward innovation and entrepreneurship within our 6 sites and extramural researchers’ laboratories. 

In parallel, a separate strategic approach that is organized by the Parker Institute leadership and site directors and codirectors takes place at our scientific retreats. Teams have been created in several key areas, including best-in-class T cells for adoptive immunotherapy, checkpoint resistance, antigen discovery, and tumor microenvironment to identify key focus areas for collaborative efforts. This strategic mapping exercise leads to large collaborative groups—in some cases 15 or more different labs—working together on a particular problem or a large clinical trial in which all or most of the sites participate, often in partnership with industry to study combination and novel immunotherapies or coordinated research efforts. Four or five such projects are currently underway. 

Judging Progress

How are you assessing the progress each center is making?

We ask for brief, one-page updates of the work once a year so we can monitor research progress and invest in promising results. One of the core principles of the Institute is to avoid putting a heavy bureaucratic burden on our investigators. We believe strongly that bureaucratic burdens have a negative impact on research efforts by our investigators. And, frankly, in the Parker Institute, a lot of the accountability comes from participating together in our retreats, discussing each other’s work, and sharing early results. Being around a lot of very exceptional peers is as good a way as any to judge the work we are all doing.

Facilitating Progress in Immunotherapy

How will the Institute’s partnership with these particular centers facilitate progress in cancer immunotherapy?

Science in general has become very expensive and complicated, and cancer immunotherapy is no different. The interdisciplinary nature of the research, the need to access new technologies and instruments, and the challenge of accessing patients and drugs have come together to increase the difficulty for each scientist to innovate, create, and discover. 

The greatest challenge to individual scientists today is bringing together all the resources necessary to address the most challenging questions in immunotherapy. We are committed to reducing the barriers and helping researchers work together in a more efficient, seamless way. Our agreements with each institution allow for the early sharing of ideas, data, and discoveries as they are made, as well as access to the most innovative technologies and novel drugs. 

I believe the combination approaches are going to be quite varied, positive, and efficacious as we learn the rules. The future is clearly bright, and with the support of Sean Parker and other philanthropists interested in ‘hacking’ the research enterprise, I am more optimistic than ever that we can change the course of cancer and other devastating diseases.
— Jeffrey Bluestone, PhD

Another way we are facilitating research progress is by bringing together a collection of incredibly smart people, sticking them in a room, and asking them, “What are your wildest ideas? What would you wish you could do to explore and investigate those ideas if you didn’t have to compete in the current funding environment or wait a year or more for funding?”

The Parker money allows a different type of research effort, one that is not as constrained as other funding efforts. When you give researchers that kind of flexibility, it gives them permission to think big and audaciously and to be willing to fail, knowing that the study is well designed and informative. The researchers in the network learn from the outcome and then redeploy the resources in new ways. In that kind of environment, people feel that they can try blue-sky ideas in ways they wouldn’t have been able to in the current funding environment. 

Finally, this open and interactive sandbox, filled with new toys including instruments, novel technology partnerships, and access to drugs—both approved and in the pipeline—creates a chemistry built on a common, shared scientific and programmatic mission with an environment where the scientists can freely share information and collaborate. New thinking and ideas come out of that kind of collegial atmosphere, which I’m hoping to exploit.

Understanding Cancer Biology

One of the conundrums of immunotherapy is that it does not work for every patient. Is there a greater understanding of why immunotherapy works for some patients and not others?

That problem is certainly a major focus of our strategic plan of research projects. We want to answer not only why immunotherapy works in some people and not others and why its effects last forever in some people and not others, but also why it is effective in some cancers and not others. All of those are key questions.

I don’t think we are going to solve these challenges by just mixing and matching different drugs and trying approaches in an ad hoc empirical way. We are going to make advances by deeply interrogating the underlying mechanistic principles that determine what is happening at the tumor site and throughout the body.

One of the most important aspects of our work is making sure that we get access to critical biospecimens, including tumor tissues, and that we interrogate them deeply with new technology and informatics approaches that can convert data into knowledge combining data from across all the sites and all the trials. 

We hope to combine data from multiple approaches, including genomics, proteomics, imaging, and, of course, clinical information in ways that perhaps no individual site or scientist can accommodate. At the end of the day, we are only going to get answers to those questions if we have a much deeper understanding of the underlying biology and biochemistry in the tumor and its environment. 

Reducing the Cost of Care

In light of the high cost of immunotherapeutics, what is the expectation for immunotherapy—that it will cure a person’s cancer or convert it to a chronic disease?

I can’t predict what will happen in the future. I can say we definitely believe that over a period of time we will have many more patients who achieve permanent cures. That is an aspirational goal, and if in 5 to 10 years we haven’t achieved that goal in more patients than we have now, we will not have met one of our major objectives. 

The implication of achieving more cures is that we will see decreases in health-care costs, not only because patients won’t have to take cancer therapeutics for the rest of their lives, but because they won’t be suffering relapses and need ongoing care.

I also think if we can get much better at predicting who to treat, when to treat, and what treatment to use, that will also reduce the cost of care, because failures are very expensive, and moving from one drug to the next drug to the next drug is very difficult for patients to deal with and damaging to patients system-wide. 

I’m hoping that the whole cost structure of drugs will change as we move to combination therapies, which I strongly believe is going to be necessary in many settings. As we do that, we have to come up with new cost models that patients and insurance companies can afford, but that also provide pharmaceutical companies with continued incentives to do the great research they are doing to develop many of these new drugs.

Finally, we can imagine a time when—just as we have done for cervical cancer—we create a vaccine for other cancers. This outcome will be the safest, least toxic, most effective, and least expensive treatment, but one that will take many years to achieve in a few cancers at best. 

Changing the Course of Cancer

Are you imagining that achieving durable remissions and even cures in patients will take a combination of immunotherapy and conventional chemotherapy? 

We are still in the early days of figuring that out, but what we are learning is that perhaps a number of the preexisting therapies—whether radiation, chemotherapy, or targeted therapies—are potentially participating in the efficacy of immunotherapy, and by themselves generating damage that leads to antigen release, thereby boosting the immune response. In addition, these standard treatments perhaps induce additional mutations, allowing the immune system to recognize cancer cells as foreign invaders. 

Thus, rather than immunotherapy being the second- or third-line treatment, it is likely to become the first-line treatment in multiple cancers with chemotherapy, targeted therapies, and radiation therapy becoming adjunct therapies, perhaps at lower doses to reduce toxicity, but providing the added immunogenicity. The bigger focus for me is on how we are going to maximize the use of immunotherapies both to initiate and promote the immune response we are talking about, including combinations of different checkpoint inhibitors, immune adjuvants, and drugs that modify the tumor microenvironment. 

Right now, we are effectively using CTLA-4 and PD-1 blockade in melanoma and lung cancer, and that is going to continue, but there are other potentially useful checkpoints on the horizon. Adjuvant-like or activating molecules being tested now have initiated an immune response in laboratory studies and in the clinic; they include innate immune activators, such as TLR [Toll-like receptor] agonists, anti-CD40, and even oncolytic viruses, which together with checkpoint inhibitors will be effective in different types of cancer. There are also vaccine opportunities where we mix vaccines with some of these immunopotentiating drugs to achieve more robust and profound immune responses in patients. 

I believe the combination approaches are going to be quite varied, positive, and efficacious as we learn the rules. The future is clearly bright, and with the support of Sean Parker and other philanthropists interested in “hacking” the research enterprise, I am more optimistic than ever that we can change the course of cancer and other devastating diseases. ■

Disclosure: Dr. Bluestone is President and CEO of the Parker Institute for Cancer Immunotherapy.

References

1. Murray FE: Evaluating the role of science philanthropy in american research universities. National Bureau of Economic Research Working Paper No. 18146, June 2012. Available at www.nber.org/papers/w18146. Accessed November 8, 2016.

2. Anft M: When scientific research can’t get federal funds, private money steps in. The Chronicle of Philanthropy, February 8, 2015. Available at www.philanthropy.com/article/When-Scientific-Research/151777. Accessed November 8, 2016.



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