A class of drugs that teaches the body’s immune system to attack cancerous cells is being hailed as the beginning of a “new era for cancer treatment.” Experts believe it could be the biggest step forward since chemotherapy, providing a potent new weapon in the fight against cancer.
An international study found that a combination of two drugs that helped allow the immune system to fight the cancer — ipilimumab and nivolumab — reduced tumor size in almost 60% of individuals with advanced melanoma, the deadliest form of skin cancer. In a separate study, nivolumab was shown to reduce the risk of lung cancer death by more than 40%.
Both ipilimumab (Yervoy) and nivolumab (Opdivo) are FDA-approved monoclonal antibodies, engineered in a lab to attach to a specific antigen on the surface of the cancer cells. This marks the cancer cell and makes it more visible to the immune system, signaling the body’s immune cells to mount an attack. The drugs are approved specifically for the treatment of melanoma and non-small cell lung cancer (NSCLC) that has metastasized during or after chemotherapy.
According to cancer experts, however, the results of these latest studies indicate that nivolumab and other immunotherapeutic drugs could one day become standard treatment for most types of cancer, even replacing chemotherapy.
Dr. Roy Herbst, chief of medical oncology at Yale Cancer Center in New Haven, CT, believes this could happen in the next 5 years. “I think we are seeing a paradigm shift in the way oncology is being treated,” he told The Guardian. “The potential for long-term survival, effective cure, is definitely there.”
Immunotherapy: Then and Now
Cancer immunotherapy dates back to 1891, when a New York surgeon named William Coley began injecting bacteria into patients’ tumors in the hope of triggering an immune response to the infection that would also attack the tumor. Physicians before him had noted mysterious and rare cancer remissions following infections, and Coley was eager to harness that therapeutic power.
It would not be so simple. Tumors wield many defenses against the immune system’s most powerful cancer-fighting weapon: T cells that hunt out and eliminate problem cells. Cancer cells disguise themselves and make it difficult for T cells to find them. Tumors also fend off immune attack by expressing proteins that suppress T cells in the surrounding environment.
For decades, researchers chased the possibility of a vaccine that would alert the immune system to cancer cells. But those efforts have largely failed: the only FDA-approved therapeutic cancer vaccine is a complicated and costly therapy for prostate cancer. Whether it provides a significant benefit to patients is a matter of debate.
The field turned a corner in 2011, when the FDA approved a new kind of immunotherapeutic drug. Ipilimumab binds to and blocks a ‘checkpoint’ protein called CTLA-4, which normally acts as a brake on the immune system by preventing T-cell activation. Checkpoint proteins keep the cells in check so that they do not attack normal tissue. When ipilimumab releases the brake, T cells are free to destroy tumors. So by blocking the action of CTLA-4, ipilimumab boosts the immune response against melanoma cells in the body.
However, the drug has its drawbacks: although it can rouse T cells to battle against cancer, sometimes the cells attack healthy tissue, too. Of the 540 people who took ipilimumab in the largest trial, up to 15% experienced serious side effects and seven died of immune-related events.
Still, the promising aspects of ipilimumab established the potential of checkpoint inhibitors — drugs that block checkpoint proteins — and that has prompted researchers to look at other potential target proteins.
That research led to the development of a new generation of immunotherapeutics called PD-1 (programmed cell death protein 1) inhibitors. The first member of this class, pembrolizumab, was approved by the FDA for patients with metastatic melanoma in September 2014, followed shortly by nivolumab, which gained approval first for the treatment of metastatic melanoma in December 2014 and then for advanced lung cancer in April 2015.
These drugs work by targeting the PD-1 pathway, which provides a kind of “handshake” or connection between receptors on immune cells, called PD-1, and their sister-proteins on tumor cells, called PD-L1. Checkpoint inhibitors block that handshake, which alerts immune cells to cancer cells and targets them for destruction.
Because PD-1 interacts directly with cancer cells, unlike CTLA-4, its inhibitors have the potential to be more potent and less toxic than ipilimumab — and evidence from the new clinical trials appears to confirm that this is the case.
A ‘Major Milestone’
In a phase 3 trial, an international team of researchers tested the effectiveness of nivolumab combined with ipilimumab, versus ipilimumab alone, in 945 patients with advanced melanoma (stage III or stage IV) who had received no prior treatment.
The drugs stopped the progression of cancer for nearly a year in 58% of cases, with tumors stable or shrinking for an average of 11.5 months, researchers found. This was compared to 19% of cases for ipilimumab alone, with tumors stable or shrinking for an average of 2.5 months.
“By giving these drugs together you are effectively taking two brakes off the immune system rather than one, so the immune system is able to recognize tumors it wasn’t previously recognizing and react to that and destroy them,” explained co-lead investigator Dr. James Larkin, of the Royal Marsden Hospital in the UK. “For immunotherapies, we’ve never seen tumor shrinkage rates over 50% so that’s very significant to see. This is a treatment modality that I think is going to have a big future for the treatment of cancer.”
In another trial, researchers led by Dr. Julie Brahmer, director of the Thoracic Oncology Program at the Johns Hopkins Kimmel Cancer Center, tested the effectiveness of nivolumab against standard chemotherapy with the drug docetaxel among 260 patients with NSCLC. All patients had been treated for the disease previously, but the cancer had returned and spread.
The results showed that patients who received nivolumab had longer overall survival than those treated with standard chemotherapy, at 9.2 months versus 6 months. At 1 year after treatment, nivolumab almost doubled patient survival: nearly 42% of patients who received nivolumab were alive after 1 year, compared with only 24% of patients who received chemotherapy.
The study results also demonstrated a longer period of halted disease progression for patients who received nivolumab compared with those who had chemotherapy, at 3.5 months versus 2.8 months. Overall, the researchers estimated that, compared with patients who received chemotherapy, those who received nivolumab were at 41% lower risk of death from NSCLC.
“This solidifies immunotherapy as a treatment option in lung cancer,” said Dr. Brahmer. “In the 20 years that I’ve been in practice, I consider this a major milestone,” she adds, noting that the trial results helped achieve U.S. Food and Drug Administration approval in March to treat such patients whose lung cancer progressed, despite standard chemotherapy.
While both studies show promise for the use of immunotherapy in cancer treatment, experts note that such treatments would be expensive. The use of nivolumab plus ipilimumab for the treatment of advanced melanoma, for example, would cost at least $200,000 per patient. The drugs can also cause uncomfortable side effects — including nausea, itching, skin rash, decreased appetite, constipation, joint pain, and diarrhea — and, in rarer cases, serious adverse reactions. As such, researchers say it is important that future studies determine which cancer patients would be most likely to benefit from immunotherapy.
To date, these drugs have only been approved for use in patients with melanoma and lung cancer. However, researchers say the results of these studies suggest that the immunotherapy response is likely applicable to other types of cancer, as well. “This reinforces our belief that there are common features of the relationship between the immune system and various cancers,” said Dr. Jedd Wolchok, a leading immunotherapy expert at Memorial Sloan Kettering Cancer Center.
Several pharmaceutical companies have immunotherapy drugs undergoing trials, with promising results against melanoma, lung, liver, colorectal, and head and neck cancers. Similar drugs targeting breast and ovarian tumors are in the works, as well. There is also plenty of excitement about a new range of cancer drugs which target genetic weaknesses in tumors. And most recently, scientists have combined these two approaches, using detailed genetic information about a patient’s tumor to design personalized vaccines that even show promise against drug-resistant cancers.
These are the result of our far greater understanding of the biology of cancer, and the genetic mechanisms which drive the disease. Coupled with advances in diagnostic tools, we really could be on the cusp of an extremely exciting new era in cancer treatment.