New Cancer Immunotherapy Helps Patients with Metastatic Melanoma Live Longer

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, PhD, 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, PhD

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.”

F. Stephen Hodi, MD, a clinical researcher at the Dana-Farber Cancer Institute and principal investigator on the phase 3 study, said melanoma is just the beginning. “We can explore this new treatment in many other kinds of cancer, as well.”

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, MD, PhD, 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 landmark trial has other important implications for the field beyond establishing the effectiveness of this particular cancer immunotherapy. Axel Hoos, MD, co-chairman of the executive committee of the CRI Cancer Immunotherapy Consortium, a program that seeks to optimize the development of the emerging field of immuno-oncology, and medical lead for ipilimumab at Bristol-Myers Squibb, said ipilimumab investigation represents a significant advance in how clinical studies of cancer immunotherapies are conducted and evaluated.

“The existing paradigm for evaluating the effectiveness of new cancer treatments is informed by experience with chemotherapy,” Hoos said. “The chemotherapy paradigm does not entirely account for the biology and unique mechanisms of action of cancer immunotherapy.”

To address this issue, the CRI Cancer Immunotherapy Consortium, in collaboration with international partner organizations, immunologists, and clinical oncologists around the world spearheaded the development of a new operating framework for immuno-oncology.

This new framework encompasses a clinical development paradigm that allows clinicians to more effectively investigate immunotherapies in clinical trials. According to Hoos, the ipilimumab trial results contribute to the validation of the new paradigm. “This offers a path forward for the field for more successful development of immunotherapies in the future,” Hoos said.

The Cancer Research Institute is currently testing a variety of therapeutic cancer vaccines through its Cancer Vaccine Collaborative (CVC), a joint program with the Ludwig Institute for Cancer Research. Lloyd J. Old, MD, director of the Cancer Vaccine Collaborative and director of the CRI Scientific Advisory Council, said the emergence of T-cell potentiators like ipilimumab as well as other modulators of immunosuppression has opened a new front for clinical discovery in cancer vaccine research.

“Over the past ten years, the Cancer Vaccine Collaborative has established an unprecedented understanding of the human immune system response to treatment with cancer vaccines,” said Old. “There is now considerable evidence that the body recognizes cancer as foreign, but the full force of the immune system to combat cancer is blunted by inherent safeguards that have evolved over time to prevent the immune system from attacking healthy tissue, a condition called autoimmunity that can arise when these safeguard mechanisms fail. Blocking CTLA-4 with ipilimumab removes this constraint and permits more efficient immune control of the tumor.”

According to Old, the introduction of ipilimumab and therapies that target other mechanisms involved in immune suppression launches a new era in the development of effective cancer vaccines, offering powerful new tools for overcoming the body’s restraints on generating protective cancer immunity.

“Ipilimumab represents a major step in the century old dream of incorporating the immune system in our battle against cancer,” said Old, “and learning how to maximize the combined therapeutic effects of ipilimumab with other cancer therapies, including the new targeted therapies, is the immediate challenge.”

“Our ultimate goal,” said O’Donnell-Tormey, “is to establish highly effective immunotherapies as part of the standard of care in the treatment of cancer. The recent FDA approval of Provenge and the striking data on ipilimumab show that significant progress is being made toward achieving this goal.”

“Given these recent advances,” said Old, “we can predict that therapies based on immunological principles are poised to revolutionize our understanding and treatment of human cancer. Exploiting the power of the immune system to combat cancer is now clearly within our reach.”

Reference: Hodi et al. Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine. (published online June 5, 2010)

Media Contact
Brian M. Brewer, Director of Communications, Cancer Research Institute
+1-212-688-7515, ext. 242, or [email protected]