Is all the enthusiasm around immunotherapy justified? According to Carsten Kampe, MD, PhD, from Texas Oncology, the simple answer is yes.
Not that long ago, the median overall survival of patients with advanced melanoma was about 2 years. With ipilimumab, the first checkpoint inhibitor approved by the FDA, about 20% of patients were alive at 10 years, and with the addition of nivolumab that number jumped to about 35%.
“If that’s not exciting, I don’t know what is,” said Dr Kampe at the AONN+ 9th Annual Navigation & Survivorship Conference. “Immunotherapy is revolutionizing the way we treat cancer. Patients who were given only months to live now have a chance at a cure, and ‘cure’ is not a word you often hear oncologists use when talking about advanced forms of cancer.”
When Cancer Develops
In the human body, cells divide in an orderly fashion, and only when more cells are needed. Occasionally, damage occurs to a cell, usually due to a mutation in the DNA. These mutations can randomly occur or can be induced by external forces (eg, tobacco or radiation from the sun). But in most cases, our bodies are able to recognize this “mistake” and either fix it or cause the cells to die.
In cancer cell division, these mutations in the DNA are not recognized by the immune system and do not lead to cell death. Somehow the cancer cells have learned how to evade the immune system, or the immune system is simply not strong or smart enough to recognize these abnormal cells, he explained.
“Cancer cells are not foreign invaders attacking us from the outside like viruses or bacteria,” said Dr Kampe. “They’re derived from normal cells, but they’ve lost their ability to behave normally.”
The first mutation may not cause cancer, but with successive mutations the cells become increasingly abnormal and take on the characteristics of cancer—uncontrolled growth and the capacity to spread to other organs with the ability to kill the host.
The Role of the Immune System
“The Internet can be a scary place, especially if you have cancer,” he said. “There you will find descriptions of the barbaric ways we still treat cancer. We slash with surgery, we burn with radiation, and we poison with chemotherapy. It sounds horrible, and for the most part, it is. We certainly need to find new and better ways to treat cancer.”
Masses of patients have already recognized the importance of the immune system in the fight against cancer. According to Dr Kampe, many patients go to great lengths to try to improve their own immune system in the hope it will favorably impact their prognosis. They take supplements, avoid sugar, and buy expensive concoctions. “But there’s insufficient evidence that any of this really works,” he noted. “If it did, we’d call it medicine.”
Unfortunately, many patients forego potentially curative treatment in favor of unproven alternatives. Recent estimates show that 40% of Americans believe that alternative medicine can cure cancer.
“But what if our patients are right, at least in theory?” he asked. “What if, instead of attacking cancer cells, we unleashed the power of the immune system that we already have in place? How exciting would that be? Well, that time has come.”
In 2011, the first checkpoint inhibitor was approved by the FDA for malignant melanoma, and by 2013, cancer immunotherapy was declared the breakthrough of the year by Science magazine. “The world began to take notice,” he said. “And since then, progress has been fast and furious.” At least 7 checkpoint inhibitors have now been approved for treatment of a variety of cancers, and the list is growing all the time.
“Is this the holy grail of cancer treatment? Some people think so, and many patients are depending on it,” he said.
How Does the Immune System Fight Cancer?
The fundamental property of the functioning immune system is the ability to distinguish “self” from “nonself.” T cells make up only a small fraction of the white cells in our bodies, but they’re constantly looking for invaders. Each T cell is capable of recognizing only 1 foreign invader, or antigen. When the body is exposed to a new antigen, the T cell that recognizes it needs to expand rapidly to engage in the fight and hopefully save the host. The immune system then goes into overdrive, similar to flooring a gas pedal in a car.
The immune system can easily recognize foreign invaders, but these are obvious “nonself” invaders, as opposed to cancer cells that look very much like normal cells. So, human T cells use an elaborate system to recognize and attack these cancer cells. “And once the immune system learns to attack, it remembers and is always ready to beat down the enemy if and when it tries to come back,” he said.
But in addition to having accelerators, the immune system also has brakes, or checkpoints. T-cell accelerators are needed for full-blown immune response, while T-cell brakes are needed to modulate that response. “There’s an intricate balance between the accelerators and brakes needed to attack foreign invaders and cancers, while avoiding the excessive activation that could lead to autoimmune destruction of healthy cells,” he explained.
Once these checkpoints were discovered, scientists began to ask what would happen if those brakes were removed and that interaction was blocked. “Patients are now getting infusions of antibodies called checkpoint inhibitors that seek out and selectively attach to these receptors, get rid of the brake, and allow the T cells to go on and kill the cancer.”
The 2018 Nobel Prize in Medicine was awarded to cancer immunotherapy pioneers Tasuko Honjo and James P. Allison. A press release issued by Nobel Media stated that “checkpoint therapy has now revolutionized cancer treatment and has fundamentally changed the way we view how cancer can be managed.”
“Did I mention how exciting this is?” Dr Kampe emphasized.
Immunotherapy has finally found its place in the management of cancers, he said. “While there’s still much work to be done, the future is looking brighter every day. It’s an exciting time for research scientists and oncologists, but especially for our patients.”
“But it’s still early times,” he said. “We’re still learning how to best use immunotherapy, and these treatments don’t work for everyone.” Some people don’t respond to treatment, and others have serious or life-threatening side effects. Additionally, the “outrageous” cost of immunotherapy places it out of reach for the majority of patients.
Side effects are predominantly inflammatory in nature, and any organ can be affected. As a result, “Oncologists have had to learn to become immunologists, endocrinologists, and rheumatologists,” he said. But these treatments are easy to administer and are generally well tolerated, as they are not a “poison” (no hair loss, etc).
According to Dr Kampe, some questions remain to be answered: If immunotherapy doesn’t work for everyone, can we predict who it will work for? What are the mechanisms of resistance? Can these drugs be given to patients who already have autoimmune disease? How do we best provide this therapy along with other therapies? How do we control cost? He maintains that these questions will, eventually, be answered.
“Immunotherapy gives great hope, even in late-stage disease,” he said. “But best of all, it has given oncologists the chance to use the word ‘cure’ more often.”