Things settled down again after the second operation – but not for long. And when a cancerous tumor was detected on his person for a third time, Ben-Shabbat began seeking answers elsewhere. "I saw a doctor who told me that more surgery was a waste of time, and he sent me for chemotherapy. I had four treatments, which destroyed a portion of my liver. After that, they gave me a biological drug that damaged my lungs. I felt like my time was running out. When another metastatic growth, which bled, appeared on my head, they sent me to Sheba Medical Center. The doctor said to me, 'They're doing a study there on cases like yours. Perhaps they'll agree to treat you.' I called and was told they were full up. Two days later, they called to say that one of the candidates had decided to leave, and that if I want, the place is mine."
And thus Ben-Shabbat began a series of IV treatments with a new revolutionary drug, which works on the body's immune system. The results, he says, were astounding. "The bleeding from my head ceased completely already after the first treatment," he recounts. "The tumor showed signs of shrinking already after the second and third treatments. And by the fifth and sixth treatments, I was already feeling well again."
Shortly thereafter, Ben-Shabbat was back to his usual self. "I live a totally normal life today," he says. "I come and go, and visit my children and grandchildren. I wish such a life on all of the people of Israel. I do a full-body CT scan every six weeks, and everything comes out clear. I've been reborn thanks to the drug I received."
Known as Keytruda, the drug that halted Ben-Shabbat's aggressive cancer is viewed today as the great hope for patients with metastatic melanoma, and just recently received US Food and Drug Administration approval. According to many experts in the field, Keytruda is likely to lead to a significant breakthrough in the treatment of cancer.
Unlike in the past, the innovative treatment does not focus on trying to destroy the malignant tumor by means of dangerous chemical drugs that come with serious side-effects. Instead, it serves to initiate gentle and sophisticated manipulations of the body's natural immune system, with the purpose of spurring it on to attack and destroy the cancerous cells itself. If the new treatment mechanism, known as immunotherapy, lives up to expectations, the world of oncology could undergo a real revolution within just a few years.
"The new drug creates real potential for curing one of the deadliest forms of cancer, at the negligible cost of light and tolerable side-effects," says Prof. Jacob Schachter, head of Sheba Medical Center's Ella Institute for Melanoma. "Moreover, it completely alters the working assumptions in oncology treatment, as its working mechanism is effective in the war against other types of cancer too. There's no doubt today that the holy grail of oncology lies in immunotherapy, which helps the body's immune system to destroy the tumor's cells itself.
"At this stage, we can only imagine the therapeutic potential of a combination of a number of such drugs, each acting on a different system, and some of which are already at an advanced stage of development. Among doctors, too, the scope of the breakthrough has yet to be digested."
Malignant melanomas usually start on the skin; but in rare instances, melanomas may also appear in the mouth, iris of the eye, retina at the back of the eye or under the fingernails. In 2011 in Israel, 1,469 new cases were diagnosed, with only one-third detected at an early stage at which the chances of a cure are high. That same year, 188 individuals succumbed to the disease.
Israel today ranks among the 20 countries in the world with the highest morbidity rates for melanoma, with the list headed by Australia, New Zealand, the United States and Britain. According to the International Agency for Research on Cancer, the mortality rates from the disease in Israel are even higher – the mortality rate among men is the eighth highest in the world, and the tenth highest among women.
Some 250 of the newly diagnosed melanoma patients in Israel every year suffer from metastatic tumors – in other words, conditions in which the cancer has already spread to other organs. Until just a few years ago, the average lifespan of such patients was just 6-7 months. The medical sentence facing these patients was cruel and quick.
"The options to treat metastatic melanoma were very limited up until a few years ago," says Prof. Schachter. "There was chemotherapy, the efficacy of which was practically non-existent, and there was a certain type of immunotherapy that had severe side-effects and was used by very few medical centers around the world. Around one-fifth of patients responded to this drug, and about five percent were cured."
The biological drugs entered the fray over the course of the past decade and heralded a marked improvement in terms of efficacy in treating certain types of malignant tumors; but they, too, failed to provide the optimal answer.
"The main problem with the biological drugs is that their quickly fades," explains Prof. Schachter. "Some are very helpful in the initial stage; but following treatment for several months, the tumor learns to live with them and bypasses them. The cancerous cell insists on being cancerous. When you block off one course of action from it, it evolves another. The short active time of these drugs severely hampers their efficacy."
Unlike chemotherapy, which is designed to destroy the malignant cells by means of chemical drugs, immunotherapy does not go to work on the tumor itself, but rather the healthy cells of our immune system. The new therapy centers on the knowledge that cancer cells are produced in our bodies all the time, and are immediately destroyed by the immune system. In other words, our bodies have the ability to destroy such cells, but sometimes lose this ability for some reason. Immunotherapy is designed to act in various ways to restore this lost ability.
"Every second, our bodies produce defective cells that do not follow the regular rules of the body," says Dr. Gal Markel, chief scientist at Sheba's Ella Institute. "One of the jobs of the immune system is to locate these defective cells and to destroy them. This process occurs on a daily basis in each and every one of us, but sometimes things go wrong. For various reasons – genetic or environmental – irregular cells that are a little more durable can be produced."
According to Dr. Markel, the immune system studies the new cell and adapts itself in an attempt to destroy it, but the cells, too, respond accordingly, and thus survive. This process, in which cancerous cells remain under the control of the immune system in some kind of mutual balance of terror, can continue for years.
"This means that a cancerous process already exists in the said individual, although we do not see it yet," Dr. Markel explains. "The individual in whom the process is underway is already ill with cancer, as his body already contains a small number of cancerous cells; but it doesn't manifest itself clinically. Eventually, these cells manage to develop absolute durability towards the immune system, and then the disease appears.
This means that when I, as a doctor, see a patient who has just been diagnosed, his immune system has already lost the ability to control the cancer. When a woman feels a lump in her breast, it's a sign that her cancer cells have already defeated her immune system, and that the delicate balance between the system and the rogue cells has been upset. The moment this happens, the cancer begins to run rampant."
Remove the brakes
For years, researchers were unable to crack the secret behind the mechanism that causes the immune system to stop destroying the dangerous cells. They struggled to understand what makes a system that destroys such cells on a regular basis and successfully fights off bacteria and viruses suddenly throw in the towel. In an effort to restore the immune system's lost power, researchers sought to strengthen it in various ways – but mostly failed, due, among other reasons, to the severe side-effects of the treatments.
"The efforts to activate the immune system by force failed because the fundamental problem does not lie with the system itself, but in the fact that the cancer can withstand it," says Dr. Markel, who delivered an address on the subject last week at the TEDMED conference on innovativeness in the field of medicine. "An instance in which a cancerous tumor develops is not an instance in which the immune system has stopped functioning, as was thought in the past, but rather a case of the cancer managing to effectively avoid it. The big revolution offered by the new drugs, some of which are still in the developmental stage, is that they help the immune system in various ways to snare the cancerous cells that try to slip under the radar."
One of the elements that plays a vital role in this critical game of cat-and-mouse between the immune system and the malignant tumor is the body's natural restraint mechanism, which prevents the immune system from attacking and destroying the body's organs. In some instances, these "brakes," which are designed to protect the body, prevent the immune system from attacking the cancer cells. "In order to get the immune system to destroy the rogue cells, the brakes must be removed," says Prof. Schachter. "There are various molecules that function to significantly restrain the operation of the immune system's cells. Neutralizing these molecules does away with the most significant obstacle."
One drug that functions in such a way received FDA approval some three years ago. Keytruda, which was recently approved, is the second drug that has the ability to neutralize the immune system's natural brakes. "There are other elements that help the cancer cells to survive in the body, but the brakes are a critical element," Prof. Schachter explains. "Once they are out the way, the system begins to function like crazy. The new drug is more effective than the old one; it has fewer side-effects; and it works very quickly. Within weeks, the tumors shrink and the patients go back to living normal lives."
According to FDA figures, some 69 percent of patients treated with the drug survived for at least a year after their illnesses were diagnosed, while 62 percent survived for at least 18 months. This constitutes a real revolution for patients who had previously hung on for just a few months from the time the disease was diagnosed. The hundreds of patients who have been treated over the past two years at the research's branches at Sheba and Hadassah Medical Center serve as living and breathing proof of the success of the new method of treatment.
One of them is Radislav Babin, 57, an engineer born in Belarus who contracted melanoma in 2009. "He had a brown mole on his leg that suddenly started to bleed," his daughter, Vicky, recounts. "The doctors did a biopsy and it turned out to be a melanoma. He underwent surgery to have the mole removed, and everything looked fine at first. But a year and half later, he had metastatic growths in his groin. He underwent another operation, and then he was told to expect more metastatic tumors, and that in fact there was nothing left to do."
Some two years ago, Vicky heard about the experimental treatment for melanoma at Sheba. Babin immigrated to Israel and began treatment with Keytruda last October. He reports to the hospital once every two weeks for a full day of therapy, after which he suffers from occasional tiredness – "nothing very significant," Vicky says. "He works in a factory and looks fine; the only thing is that he is tired sometimes."
Until now, the CT scans he undergoes periodically have shown no sign of the illness.
"There are dozens of success stories about seriously ill patients who had exhausted all the conventional forms of treatment and for whom no help was available, and now they are living with the disease," says Prof. Schachter. "I have one patient who works in the cosmetics and make-up department of a large store: Her treatment was a success and she is back at work fulltime. She looks and feels wonderful, and you wouldn't know she is sick. Another patient, an artist, suffered from metastases of the disease from head to toe; not a single place in his body was clear. He also received the drug, and all the metastases disappeared completely. It's amazing. Another patient was referred to us from another hospital with subcutaneous lumps of the tumor that were bleeding. Today, his CT scans show nothing at all. The disease has simply vanished. On the other hand, there are also heart-wrenching stories about young patients who were not suitable for the research and who died."
Studies presented at an oncology conference in Chicago in June show promising findings vis-à-vis the use of the drug in treating other types of cancer, including head-neck tumors, lung cancer, stomach cancer and bladder cancer. Nevertheless, despite the great deal of excitement and optimism with respect to the future, doctors are trying to speak in precise terms and steer away from the use of the term, a cure.
"There are instances of total recovery, but only among a minority of patients," Dr. Markel says. "We have blazed an interesting and promising trail; the light at the end can already be seen, but we are still inside the tunnel."