Paradigm Shift: Cancer

Lloyd J. Old, Father of Modern Tumor Immunology, Dies at 78

This past week has been one of loss and reflection at the Cancer Research Institute, as we began to cope with the news of the death of our founding scientific and medical director, Lloyd J. Old, M.D., a beloved leader, mentor, and friend who passed away a week ago today at age 78. That it was cancer that ultimately claimed his life underscores the urgency of the work Lloyd dedicated himself to his entire, illustrious career.

The Cancer Research Institute was a home to Lloyd--an organization that was central to his vision for establishing immunotherapy as a new, safer, and more effective way to treat cancer. Under his leadership from 1971 to 2011, CRI invested more than $200 million in research grants to immunologists and tumor immunologists around the world, with the goal of learning how to understand the immune response to cancer and one day develop treatments to boost that response and help cancer patients conquer their disease. Thanks to Lloyd's vision and dedication to this field, that day has dawned, and cancer patients now have access to a growing number of treatment options based on the immune system.

Lloyd made sure to leave CRI in good scientific hands before his passing, carefully selecting his successors, with the approval of our Board of Trustees. In this time of transition, we look forward to carrying Lloyd's vision forward in the decade ahead.

In the meantime, we grieve the loss of an amazing man who filled our days with inspiration, laughter, and wisdom. We will be dedicating our upcoming annual report to Lloyd, and plan to hold a memorial service in the coming months in conjunction with the Ludwig Institute for Cancer Research (LICR) and Memorial Sloan-Kettering Cancer Center (MSKCC), two other institutions that were dear to Lloyd throughout his career.

The Scientist recently published this very nice write-up on Lloyd, and the New York Times also published its obituary of this influential man who has been instrumental to bringing a new class of cancer treatments to patients. Also here is our obituary we placed in the Times last week, and here's another obituary placed by MSKCC. LICR also published this beautiful tribute to Dr. Lloyd Old.

Please take a moment to get to know more about him. We all owe him a great deal of gratitude for all he's done.

Translating Targeted Cancer Therapies into the Patient Setting

Nausea, vomiting, and hair loss are just a few of the cancer treatment side effects that all cancer patients dread. These unwanted effects come from the non-specific destruction of fast dividing cells, which is not only a hallmark of cancer cells, but also exhibited by hair follicles and the cells that line the GI tract. I think all cancer patients would herald the development of therapies that are more specific to their particular cancer and therefore less destructive to the normal cells of their body.

Newer, targeted therapies aim to destroy only cancer cells by homing in on cancer-specific cellular pathways or markers that do not appear in normal cells. To date, however, targeted therapies have not been a panacea for cancer patients. We have come to learn that only a subset of patients seem to posses the pathway or marker for which these therapies are targeted. Therefore, it is important to make sure that a patient has the right kind of cancer and associated markers to benefit from a targeted therapy.

I was dismayed to read in a recent published report in the journal Cancer that one such therapy, Herceptin, may not always be given to the right patients. Herceptin only works in women with HER-2 positive breast cancers, about twenty percent of all breast cancer patients. Results of this recent study found that up to two thirds of patients with aggressive breast cancer had no documentation in insurance records of having the genetic test done that would determine if their tumors were HER-2 positive. This suggests that many women who could benefit from the drug are not receiving it and some women might well be getting the drug with no hope that it would be effective. Clearly, this is not the best scenario.

As we move closer and closer to personalized medicine and scientists increase their focus on identifying new biomarkers that will enable us to determine which treatments will be most effective in which patient population, we need to address how this cutting edge knowledge gets translated into practice. Healthcare delivery is beyond the mission of the Cancer Research Institute, but as an organization that has helped to fund the biomedical research that has led to the explosion of knowledge poised to revolutionize cancer therapy, it is a serious concern. We can’t afford to waste this innovation.

Cancer Vaccines in the Media: Getting the Full Story

I am pleased that therapeutic cancer vaccines were described in such a positive light in a recent Time article. In my view, the more attention given to the topic of developing immunotherapies like cancer vaccines, the better. The Cancer Research Institute is a public charity that relies completely on the generosity of philanthropic donations to help it sustain the science of cancer immunotherapy, and the organization stands to benefit from increasing general awareness of the promise and near-term reality of what we and others in the field see as a new, “fourth modality” of cancer therapy (the other three modalities being surgery, radiation, and chemotherapy). Our hope is that the media’s accurate and complete explanation of cancer vaccines will propel the public into realizing that their contribution to this research is having a real and tangible impact on cancer treatment.   

Alice Park, the article’s author, does an excellent job of describing in very understandable terms not only how a vaccine can train the immune system to attack a given target, but also the challenges that researchers have encountered when they try to manipulate this innate talent of the immune system against cancer. She also gets it right when she notes that a truly effective vaccine must (a) make cancers more recognizable to the immune system and (b) also counteract natural immune suppression generated by the tumor or by the immune system itself as part of its self-protective checks and balances. It is the duality of these requirements that is responsible for the multi-decade, valiant, but disappointing effort to create cancer vaccines that can stimulate the immune system to naturally destroy existing cancers, protect against recurrence, and increase survival.  

In retrospect, the first generation cancer vaccines from the 1980s and 1990s failed because we hadn’t learned enough yet about immune function and tumor evasion. Intuitively, isolating tumor cells, inactivating them, and injecting them back into patients as vaccines seemed like a good way to rev up the immune system to mount an attack. But we now understand that an effective cancer vaccine requires a multi-component formulation to achieve a targeted and sustained immunological attack against cancer. This ideal vaccine contains tumor antigens (cancer-specific markers that the immune system can recognize and attack), immunological adjuvants (agents that non-specifically awaken the immune system and enhance the immune response to an antigen), delivery systems (the means by which the vaccine is presented to the immune system), and modulators of immunosuppression (agents that prevent the desired vaccine-induced immune response from being shut down).

What Park does not include in the article is a description of the iterative approach that is required to develop a fully effective, multi-component vaccine. Researchers must coordinate their efforts to analyze and compare the intricate immunological effects of different experimental vaccines in order to determine which combinations of agents work best for different forms of cancer.  

The Cancer Research Institute recognized that identifying optimal combinations of multiple vaccine components is a highly complex and time-consuming clinical task. In 2001, in partnership with the Ludwig Institute for Cancer Research, we created the Cancer Vaccine Collaborative (CVC) in response to the inherent challenges and lack of commercial incentives for industry to address them. The CVC is a unique, coordinated global network of clinical trial sites with special expertise in immunology, conducting parallel, single-variable, early stage clinical trials to identify the optimal composition of successful therapeutic cancer vaccines. To date, the CVC has conducted more than 40 clinical trials involving nearly 700 patients and agents from almost 20 different companies, and has generated valuable insights into how an ideal therapeutic cancer vaccine must be designed and delivered.  

Researchers in the field believe that it is only through a concerted and strategic effort such as the CVC that the full potential of the immune system will be realized and vaccines will be developed that achieve substantial tumor regression, prevent recurrence, and help patients maintain lifelong control of their existing cancers.

The cancer vaccine field would benefit significantly if the need for iterative research were included in media coverage of the field among the challenges to progress in cancer vaccine development. More public awareness of this issue could generate more support for the researchers who are working together to overcome these challenges. Companies engaged in cancer vaccine development would benefit from the new knowledge these scientists discover about cancer vaccine optimization. Ultimately, cancer patients looking to all of us to deliver the next great advance in cancer treatment would be the biggest winners.

NCI Is Crucial to Scientific Progress--And So Are Nonprofit Health Research Funders

A recent article by Gina Kolata in The New York Times (June 28, 2009) called the National Cancer Institute’s grant system “a major impediment” in our fight against cancer.

I disagree.

NCI plays a vital role in keeping American biomedical research going and fuels the basic discovery upon which cancer therapies will be developed.  While there is clearly a need for both innovative and risky science—and NCI could certainly fund more research that would fall in these categories—the research funded by NCI does have critical value.  The need for funding of projects that are conceived and guided by out-of-the-box thinking does however exist. I believe non-governmental, not-for-profit organizations can play a greater role in meeting that need.  

As the major funder of biomedical research in this country, the federal government, through the National Institutes of Health (the National Cancer Institute is one of NIH’s 27 Institutes/Centers), does keep America’s academic scientists in business.  In the vast majority of instances it is federal grants that provide the salary lines for researchers at major universities and medical centers.  Without NIH/NCI they would not have jobs, so in that sense the grant system is a jobs program, as Kolata states.  But where would U.S. science be without this line of funding?  These same researchers are the engine behind basic scientific discoveries.  It is from these research efforts that both the incremental building blocks of knowledge—basic understandings about cellular and molecular functioning in healthy and diseased states—the goals of many “small projects” and the AH HAH moments of serendipitous discoveries come.  Together they propel the field.

But is there a need to fund more innovative and riskier science?  Definitely.  With scientists worried about job security and the survival of their laboratory and the young researchers in it, however, can they risk submitting such proposals to NCI when the funding line for even the safer proposals is dismally low?  Probably not.  

So how can the system change to satisfy these disparate goals?  Is this where non-governmental funders of biomedical research come in?  I’d like to think so.  

The Cancer Research Institute as an independent not-for-profit has always funded scientific excellence and innovation.  Innovation with excellence is the mantra that perhaps more and more not-for-profits should embrace.  To truly have an impact on the overall system it would require all charitable funders to band together to fill the niche.  

Since 1971 NCI has spent $105 billion on research.  In comparison CRI has awarded $194 million—a considerable difference in scale.  But if NCI’s dollars that keep the laboratories in this country running by providing salaries and infrastructure and supporting excellent “safe” yet essential research, can be supplemented with private not-for-profit dollars for the chancier, imaginative, and less likely to succeed research, then we all win.

Gene Patents: Crucial to Academic Cancer Vaccine Research

A recent article by John Schwartz in The New York Times (May 13, 2009) reported on an American Civil Liberties Union organized suit against Myriad Genetics and the Patent Office challenging the right to patent a gene. As cited in the article, “The coalition of plaintiffs argues that gene patents actually restrict the practice of medicine and new research.” 

While I understand why the idea of gene patenting is controversial and in some cases may pose an obvious roadblock to medical progress, without it the Cancer Research Institute could not have initiated its efforts to develop a therapeutic cancer vaccine through our Cancer Vaccine Collaborative. 

The Cancer Vaccine Collaborative is a novel model for clinical research that was created by a partnership of the Cancer Research Institute and the Ludwig Institute for Cancer Research. The Collaborative conducts in an academic setting coordinated early-phase clinical trials aimed at learning how to immunize against cancer by validating molecular targets, testing new vaccine strategies, and correlating immunological responses with clinical benefit. 

Over the past eight years, the Collaborative’s efforts have focused on how best to construct a cancer vaccine that delivers the most impactful immune response. To accomplish this goal, various vaccines have been tested that center on a single cancer marker (or antigen) called NY-ESO-1 combined with a variety of deliver systems and immune modulators. 

These delivery systems and modulators—the various potential components of the vaccine that need to be brought together and tested in a comparable fashion—are often owned by biotechs and pharmaceutical companies. Lucky for the Cancer Vaccine Collaborative the Ludwig Institute for Cancer Research owns the patent for NY-ESO-1. This has allowed the Cancer Vaccine Collaborative to negotiate with no less than eight biotechs and pharmas access to their proprietary agents in return for a non-exclusive license to NY-ESO-1. Without this leverage, the Collaborative could not have carried out the clinical trials that are bringing us closer to creating and effective therapeutic cancer vaccine. 

The sword of intellectual property (IP) thus cuts both ways and must be wielded carefully. Should gene patenting be found by the courts to be unethical and rendered illegal, such a ruling would have serious ramification for academic research initiates. IP is often the only entry that academic researchers have to negotiations with for-profit companies for key agents that are required for them to carry out their work. Academic initiatives like the CVC would lose a potent negotiation chip with companies if it did not control the patent to NY-ESO-1, this in turn would severely hobble our research efforts. Clearly, in some circumstances gene patents do not hinder new research, but instead are actually vital to scientific and medical progress.

Translational Research is a Two-Way Street

The circular loop clinic to lab to clinic is the most effective way to advance research that can most benefit patients. Oftentimes these two universes are segregated by laboratory researchers undertaking open ended discovery with no thought to potential application to a given disease state and clinical researchers looking to develop effective therapies without exploring the underlying mechanism of a therapy’s success or failure. Linking these two endeavors in a more directive and iterative fashion allows for effective laboratory and clinical discovery.

A recent issue of Pullan’s Pieces reinforced this belief and my view that Cancer Research Institute’s programs need to support research in both the laboratory and clinic if we are to extract the greatest impact from the use of our philanthropic dollars. The commentary reflected that the large number of gene variations that contribute to a given disease highlights the need for the development of increasingly more personalized medicine. The author goes on to state that this in turn requires a more detailed understanding of the biology of disease.

Developing therapies for cancer and other diseases requires research on patients. In addition to studying the actual clinical responses (in cancer, for example, tumor shrinkage), much can be gleaned from the valuable blood and tissue samples obtained from patients participating in clinical trials. Often times, however, the further examination of these precious human samples generates questions on therapeutic mechanisms of action or critical cellular and molecular pathways that can’t easily be addressed in the patient or from these clinical samples. Instead, the needed understanding of the biology of the disease or the therapy can only be ascertained from the study of animal or other laboratory models. The results and knowledge obtained from this type of basic research must and should feed back into the design of the next clinical trial in humans. In this manner a two-way street of exploration between the clinic and the laboratory is established, and patients ultimately benefit.

An important role for a not-for-profit with a mission to change the course of a given disease is to create programs in laboratory and clinical research that are well integrated. In doing so, basic discoveries can best inform the design of novel therapies, and clinical discovery in humans does not end with a given clinical trial, but rather illuminates the important biological questions that need to be explored further so that treatments for patients can be refined and ultimately made more effective.