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Response to Robert Langreth's CANCER MIRACLES

February 16, 2009 | Jill O'Donnell-Tormey, Ph.D.

In his excellent cover article on the incidence of spontaneous regression of tumors in late-stage cancer patients and the link of these "cancer miracles" to the immune system and its response to cancer ("Cancer Miracles" Forbes, March 2, 2009, published online Feb. 11, 2009), Robert Langreth reports some of the most tantalizing and encouraging victories to come out of clinical trials of therapies that harness the immune system’s power to control cancer.

As CEO and director of scientific affairs of the Cancer Research Institute, a nonprofit organization founded in 1953 to foster scientific understanding of the immune system and its relationship to cancer, I was gratified to read Langreth’s compelling and accurate description of the potential of immune-based therapies to revolutionize cancer treatment and radically change—for the better—how we perceive and approach this disease.

Langreth should be commended, as should other journalists whose job it is to educate the public on important scientific and medical advances—theirs is no easy task and they deserve our praise and appreciation. They do a great service by calling attention not only to the breakthroughs that are changing the face of cancer, but also to the scientists and clinicians behind these advances, the men and women who dedicate their lives to searching out new knowledge to improve humanity’s lot. Laboratory researchers and physician scientists—these "unsung heroes"—deserve the lion’s share of credit for their discoveries, considering that their important contributions are often overlooked and undervalued, and their research efforts grossly under funded, by the very societies that benefit.

There is, however, another unsung hero without whom much of the research could not be done, the "silent but vital partner" that is the nonprofit research funding organization. As many of the immunologists and tumor immunologists who have received funding from the Cancer Research Institute have stated, were it not for funding through our predoctoral training grants, postdoctoral fellowships, investigator awards, or clinical investigation grants, these and other important discoveries might not have been possible.

The sentiment is particularly poignant considering that, next to cancer itself, the Cancer Research Institute is the strongest common thread that binds together nearly all of the patients, research scientists, doctors, biotech & pharmaceutical companies, and historical figures described in Langreth’s article. Below, I’ve outlined some of these intimate connections to show how, within a single article about the field, the footprint of the Cancer Research Institute is rather evident.

The matrix of discovery

As the foster parent and benefactor to the field of tumor immunology, and as a leading, active force within the academic and, increasingly, the industrial arenas of cancer vaccine discovery, the Cancer Research Institute is a critical component of any story on the medical breakthroughs resulting from the field of tumor immunology. We would like to show here some of the ways that CRI has promoted, funded, fostered or otherwise helped make possible the specific "cancer miracles" Langreth describes.

Let us go to the origins of tumor immunology, as Langreth does by evoking the work of the late 19th century surgeon, Dr. William B. Coley, whose observations of spontaneous tumor regression in cancer patients with fever resulting from bacterial infection led to the first experiments with what we now understand to be a form of non-specific cancer immunotherapy. After his death, Dr. Coley’s notes were catalogued and reported in a series of monographs penned by his daughter, Helen Coley Nauts, whose chronicling of her father’s work laid the foundation for what is now the burgeoning field of tumor immunology. She would found the Cancer Research Institute in 1953 to create the world’s first organization dedicated exclusively to studying how the immune system can be manipulated to treat cancer. Though her work primarily focused on her father’s methods, the organization eventually would grow in its scope to encompass the whole of basic immunology thanks to the efforts of Dr. Lloyd J. Old, a world-leading tumor immunologist who served as CRI’s Scientific Director from 1971 to 2011.

Dr. Old was a living legend within the field of tumor immunology, an award-winning scientific luminary whose intellect, passion, and mentorship have benefited many of today’s leaders in the field. His research contributions are among the most important to the field, to be sure; but it is perhaps his generosity of spirit and ability to encourage the best in others for which he is most revered by his friends and colleagues.

One such colleague is Dr. Jedd Wolchok, who Langreth reports treated Sharon Belvin with anti-CTLA-4 monoclonal antibody therapy. Twenty-five years ago, Wolchok was a freshman at Princeton University when, looking for a summer research position he met with Old, then vice president for research at the Sloan-Kettering Institute (then, as it is today, one of the premier cancer research and treatment centers in the world). As Wolchok eloquently narrated in his keynote address at the Cancer Research Institute 22nd Annual Awards Dinner in 2008, Old’s generosity and vision were a defining influence in what has since become an illustrious career of his own. Such gratitude can be multiplied many times over among the hundreds of scientists who trained under Old or who have collaborated with him.

Wolchok is one of the most dedicated members of the Cancer Research Institute community. He is director of the CRI/Ludwig Institute Cancer Vaccine Collaborative (CVC) and an associate director of the CRI Scientific Advisory Council. He has received CRI funding to support his human trials of a xenogeneic DNA vaccine that recently received USDA approval to treat dogs with advanced melanoma, and has given lectures at CRI-sponsored international and community-level conferences or special educational events.

Wolchok works closely with Dr. James P. Allison, the laboratory researcher who discovered the anti-CTLA-4 therapy described in Langreth’s article. Allison was appointed director of the CRI Scientific Advisory Council in 2011, and in 2005 he received the CRI William B. Coley Award for Distinguished Research in Basic and Tumor Immunology. Sharon Belvin, whose late-stage melanoma, Langreth reports, disappeared after several treatments of anti-CTLA-4, spoke at the Cancer Research Institute 2007 Annual Awards Dinner and shared her story of survival (read Sharon's story here). Bristol-Myers Squibb (BMS) has also agreed to provide anti-CTLA-4 to clinicians within the CRI/Ludwig Institute Cancer Vaccine Collaborative in a partnership that will provide CVC researchers with what they consider a vital component of an effective vaccination strategy and will provide BMS with valuable data on the immunological response to anti-CTLA-4 when used in combination with a therapeutic cancer vaccine.

Also mentioned is Dr. Robert Schreiber, an associate director of the CRI Scientific Advisory Council whose laboratory at Washington University in St. Louis has received millions of dollars in support from CRI. CRI featured in its 2008 annual report the work of Schreiber and colleagues Mark Smyth and Lloyd Old, who together validated and enhanced the now proven theory that the immune system can detect and destroy cancer and also plays a role in shaping, or editing, the cancer phenotype.

Dr. Glenn Dranoff, also an associate director of the Cancer Research Institute Scientific Advisory Council, Dr. Jeffrey Ravetch, a council member, and Dr. Cassian Yee, all mentioned in Langreth’s article, have received or are currently receiving funding from the Cancer Research Institute to support their laboratory or clinical research into the immune system and its relationship to cancer and who have presented plenary lectures for the Cancer Research Institute’s Annual International Cancer Immunotherapy Symposia Series. Dr. Wolf Fridman and NIH’s Steven Rosenberg have also spoken at CRI symposia about their important work.  CRI has also bestowed the Coley Award upon Drs. Schreiber (2001) and Ravetch (2007).

Langreth also mentions in his article a GlaxoSmithKline lung cancer vaccine that is currently under investigation in the largest lung cancer clinical trial ever conducted. The data from a Cancer Vaccine Collaborative trial in which the antigen used in the GSK vaccine was tested in lung cancer patients contributed to GSK’s decision to move forward with the promising therapy. Vincent Brichard of GSK, whom Langreth mentions, has also been a repeat plenary speaker at CRI symposia. In one of the greatest successes for the Cancer Vaccine Collaborative, GSK has licensed a broad portfolio of cancer-specific antigens from the Ludwig Institute for Cancer Research, CRI’s partner in the Cancer Vaccine Collaborative, including the NY-ESO-1 antigen Langreth mentions.  This prototypic and highly immunogenic cancer antigen has been the central target of cancer vaccines under investigation in the CRI/Ludwig InstituteCancer Vaccine Collaborative since its establishment in 2001.

On the subject of cancer vaccines, Langreth reports that "numerous trials of anticancer vaccines designed to train the immune system to recognize cancer have shown mostly lackluster results." The Cancer Research Institute and Ludwig Institute for Cancer Research determined that a primary reason for these poor results was a lack of complete understanding of how the immune system responds to cancer vaccination. What was needed was a model of clinical discovery where scientific questions could be asked in a comprehensive yet efficient way that would lead to optimal vaccine constructs for late-stage clinical studies.

CRI and Ludwig Institute, therefore, formed the Cancer Vaccine Collaborative, a first global network of academic clinical trial sites and immune monitoring laboratories that seek to learn through open sharing of data from centralized, coordinated, parallel, and standardized academic clinical trials how best to monitor the immune response to cancer and how best to vaccinate against cancer. Using this model network, nearly 60 clinical trials have been completed or are being currently conducted, including a multi-center randomized phase II trial.

These trials have enrolled more than 1,000 patients with a variety of cancer types, including melanoma and sarcoma, and ovarian, prostate, lung, breast, esophageal, and bladder cancers. These studies have produced an immense volume of data on the human immune response to cancer antigen-specific vaccination.

Cancer Vaccine Collaborative investigators have published more than 150 scientific papers on this subject, many of which are considered to be key studies in the field. And most importantly, patients in Cancer Vaccine Collaborative vaccine trials have experienced stabilization of disease and longer disease-free survival times than expected. The way we design and deploy investigational cancer immunotherapies is rapidly evolving, and the results, as Langreth reports, are astounding.

Completing the circle

We at the Cancer Research Institute have a long memory when it comes to immunology and tumor immunology—we are the first organization to focus exclusively on this area of research and the only to remain fully committed to it, even during those periods when it was not considered viable by many leaders in oncology. Our pioneering and field-sustaining work has led today to the validation of our vision and provided the rationale for clinical studies of cancer vaccines and other immune-based approaches to cancer treatment, control, and prevention.

We can therefore say with some wisdom that, thanks to advances in tumor immunology, dramatic patient recoveries like those described in Langreth’s article will become increasingly common—as long as the researchers that make these scientific advances possible continue to receive the funding they require. Nonprofit research funding organizations like the Cancer Research Institute are dedicated entirely to meeting this critical need. Though such organizations may provide only a relatively small fraction of the annual expenditure on health research compared to the billions spent by governments and commercial entities, our role is nevertheless an important one, especially in niche research areas like tumor immunology. In the 60 years since CRI’s founding, for example, nearly 3,000 scientists and clinicians throughout the world have relied on CRI for funding to keep their research alive.

A golden opportunity

There is here a golden opportunity for journalists to further aid scientific progress not only by introducing the public to the advances and the researchers responsible, but also by providing the public with an opportunity to become a proactive participant in scientific advance by pointing them to the charities that keep this research going. Nonprofits like the Cancer Research Institute depend on the generosity of the public to raise their operating budget every year.  In an increasingly tight economy, journalistic media coverage is an extremely valuable aid to the nonprofit’s efforts to raise awareness of its work.

Journalists are in a position to aid our efforts significantly by including mention of the important role we play in making possible these exciting advances. In showing the public how they, too, can become part of scientific advance—by contributing to the nonprofit funding organizations—journalists would help to engender a community of readers who consider themselves personally vested in the science itself.

The supportive public, we believe, will continue to look to journalists like Langreth who cover this area to keep them informed of the role they themselves are playing in advancing immunology to conquer cancer.


Originally published Feb. 16, 2009. Updated Feb. 11, 2013.

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