Phase 3 Clinical Study of a New Cancer Immunotherapy Extends Survival in Patients with Refractory Melanoma
First Treatment Ever Proven in a Randomized Trial to Extend Life for Patients Whose Melanomas are Unresponsive to Existing Cancer Therapies
(June 7, 2010 – New York, NY) The Cancer Research Institute, a nonprofit organization dedicated to the development of immune system-based treatments for cancer, announced today its celebration of a significant new breakthrough in the treatment of melanoma, the deadliest form of skin cancer. The new treatment, a cancer immunotherapy created by Cancer Research Institute Scientific Advisory Council Associate Director James P. Allison, Ph.D., is designed to “take the brakes off the immune system,” and is the first treatment ever proven to extend life for patients whose melanomas are unresponsive to existing cancer therapies.
Results from a large, randomized, multicenter phase 3 clinical study, published Saturday in the New England Journal of Medicine, confirm that the new treatment, a monoclonal antibody called ipilimumab, successfully boosts and sustains immune system responses against melanoma tumors in a large percentage of treated patients. The study also shows that the new treatment confers a survival advantage in a significant number of patients, resulting in durable protection against cancer.
According to the study report, 46 percent of patients on the trial who received ipilimumab were still alive at one year compared to 25 percent of patients on the trial who did not receive the new treatment. At two years, 22 to 24 percent of treated patients were still living compared to 14 percent in the study’s control arm. The study tested ipilimumab alone, in combination with a vaccine targeting the melanoma tumor antigen peptide gp100, and vaccine alone.
“As an organization that for nearly 60 years has focused on advancing new immune system-based cancer treatments like the monoclonal antibody ipilimumab, the Cancer Research Institute considers this new breakthrough yet another significant success for the field of tumor immunotherapy and further validation that the immune system can be harnessed to treat, control, and prevent cancer,” said CRI executive director Jill O’Donnell-Tormey, Ph.D.
In May this year the FDA approved the first therapeutic cancer vaccine, sipuleucel-T (Provenge®) for the treatment of prostate cancer. For the ipilimumab therapy, Bristol-Myers Squibb, the drug’s manufacturer, says it expects to file for regulatory approval of its new treatment later this year. If successful, the drug could be the next cancer immunotherapy to receive FDA approval.
T cells (T lymphocytes) are immune cells that play a critical role in the body’s attack against tumors. Ipilimumab represents the first in a new class of cancer immunotherapies called T-cell potentiators, which modulate the “stop/go” signals that control T-cell activation. By suppressing these “stop” signals, ipilimumab allows the T-cell response against cancer to proceed unimpeded.
Ipilimumab specifically blocks CTLA-4, a molecule that inhibits the activity of T cells. Dr. Allison showed in 1995 that CTLA-4 was a negative regulator of T-cell responses, and hypothesized that blocking it could lead to strong tumor rejection. He went on to develop a monoclonal antibody that successfully blocks CTLA-4, and conducted the early mouse studies confirming his hypothesis of anti-CTLA-4-mediated tumor regression.
According to Dr. Allison, T-cell potentiation with ipilimumab may eventually help patients with many different types of cancer live longer. “Studies have shown that the immune system can recognize, target, and attack many different kinds of cancer,” Allison said, “and ipilimumab may help to strengthen and sustain that immune response, no matter the type of cancer.”
Smaller clinical studies of ipilimumab in other cancer types, including lung and prostate cancers, suggest the treatment has clinical activity, and further clinical research is ongoing to confirm these data.
According to Jedd D. Wolchok, M.D., Ph.D., also an associate director of the Cancer Research Institute Scientific Advisory Council, a CRI clinical investigator, and one of the clinicians involved in the large phase 3 study, there currently are no approved medicines indicated for patients whose melanomas return after primary treatment.
“The study is very significant,” Wolchok stated, “as it is the first time ever that a randomized phase 3 study in melanoma has shown a new treatment to provide an overall survival benefit.”
The Nobel Foundation announced yesterday that three immunologists will receive the 2011 Nobel Prize in Physiology or Medicine for their fundamental discoveries on immune system recognition of infection. Drs. Bruce Beutler, chairman of the department of genetics at The Scripps Research Institute, and Jules Hoffmann, research director for the National Center of Scientific Research in France, will share one-half the prize, and Dr. Ralph Steinman, a professor of cellular physiology and immunology at The Rockefeller University, will receive the other half.
Sadly, concurrent with the award announcement yesterday the world also learned that Dr. Steinman passed away on Friday after a long battle with pancreatic cancer. The Nobel Foundation has decided to bestow the award posthumously on Dr. Steinman.
All three scientists have long and strong connections with the Cancer Research Institute, and we therefore take great pride in this superlative honor, which reflects both on the important contributions these individual scientists have made as well as on the prominence of immunology and, increasingly, tumor immunology, in the advancement of new approaches to the prevention and treatment of infectious diseases and cancer.
William B. Coley Award to Nobel Prize Winners
The three Nobel Prize winners are former recipients of the Cancer Research Institute’s top scientific honor, the William B. Coley Award for Distinguished Research in Basic and Tumor Immunology (Steinman in 1998, Hoffmann in 2003, and Beutler in 2006). CRI honored Dr. Steinman for his discovery of the dendritic cell, a fundamental immune system cell responsible for alerting other components of the immune system to danger from infection and cancer. Drs. Beutler and Hoffmann received the Coley Award for their independent work in identifying the toll receptor (Hoffmann in fruit flies) and toll-like receptor gene (Beutler in mammals) involved in the activation of the innate immune response. Beutler, Hoffmann, and Steinman join the list of other past Coley Award recipients who have since gone on to receive the Nobel Prize and other major scientific awards, underscoring the Coley Award selection committee’s foresight and the award’s significance as a predictor of future recognition by others outside the fields of immunology or tumor immunology.
Direct CRI Funding to Nobel Prize Winners
Ralph Steinman:
In 1980, CRI supported Dr. Steinman’s first study on the potential for dendritic cells to orchestrate immune attack on tumors. It was his first tumor immunology study, proposed at a time when few believed that the immune system could be trained to fight cancer. CRI continued to support Dr. Steinman’s lab by awarding postdoctoral fellowships to two scientists in his laboratory, Dr. Jonathan Austyn (currently a professor of immunobiology and principal investigator in the dendritic cell research group at Oxford University John Radcliffe Hospital) and Dr. Angela Granelli-Piperno (who has since published work on HIV infection in dendritic cells and the role of lymphokines in autoimmune disorders). CRI’s seed support of Dr. Steinman’s then highly unconventional idea laid the foundation for his future studies on dendritic cell vaccines for cancer.
In 1998, CRI awarded Dr. Steinman a grant to support a preclinical study of active immunotherapy against lymphoma by antigen-presenting dendritic cells. Such vaccines have since become a major focus of research and development, and Provenge™, the first FDA-approved therapeutic cancer vaccine for prostate cancer, is based on the dendritic cell vaccine technology Dr. Steinman pioneered. It has been reported that Dr. Steinman himself was a patient in a study of his own dendritic cell vaccine for pancreatic cancer, and he credited the vaccine with extending his life.
Jules Hoffmann:
Dr. Hoffmann’s exploration of the innate immune system and its activation bears central importance to CRI’s ongoing efforts to determine optimal vaccination strategies in the treatment of cancer. A critical step in successful vaccination is stimulation of the non-specific (innate) immune system—first-line responders to infection and damaged cells that provide broad protection against bacteria and fungi and also play an important role in the activation of cancer-specific (adaptive) immunity.
In addition to the 2003 Coley Award, CRI provided postdoctoral fellowship support to Dr. Hoffmann’s laboratory in 1995, to Dr. Sarah Ades for her work to clone and characterize the lipopolysaccharide pattern recognition receptor in the innate immune response of fruit flies (drosophila). Dr. Ades is currently an associate professor of biochemistry and molecular biology at Pennsylvania State University.
Bruce Beutler:
Dr. Beutler took Dr. Hoffmann’s work in the fruit fly and found the corresponding innate immune system receptor in mammals, bringing Hoffmann’s important discoveries to bear on the treatment of human disease. The Beutler lab has received CRI funding in the form of postdoctoral fellowships for Dr. Carrie N. Arnold (2007) and Dr. Amanda L. Blasius (2008), to support their respective studies of mammalian resistance to viral infection and genetic analysis of the type 1 interferon response to toll-like receptor 9. CRI also funded two members of Dr. Beutler’s lab in 2006 (Dr. Kasper Hoebe and Dr. Zhengfan Jiang) in their genetic analysis of “cancer proof” SR/CR mice from the laboratory of Dr. Zheng Cui.
We congratulate Drs. Beutler and Hoffmann on their outstanding accomplishment, and extend our congratulations to Dr. Steinman’s family as well as our condolences on their loss of a beloved family member, who was also a highly respected colleague and long-time friend of tumor immunology and the Cancer Research Institute.