Prof. Shimon Slavin: When the cells are infused into a patient, they go immediately to work because they were already trained in the laboratory to become professional killer cells capable of recognizing and destroying foreign cells.”Until recently, the prognosis was poor for cancer patients with metastatic solid tumors and blood cancer patients having a relapse following transplantation from donor stem cells. Their only options, which didn’t promise much success for a cure, were aggressive: another round of high dose chemotherapy and radiation, another transplantation – or both.

But new and experimental procedures developed in Israel that trick infection-fighting white blood cells of the immune system – lymphocytes – to better read and target diseased cells, are giving immunologists and cancer patients hope.

Forged by researchers at the Hadassah University Medical Center in Jerusalem, under the direction of Weisner Department of Bone Marrow Transplantation and Cancer Immunotherapy director and bone marrow transplantation pioneer Prof. Shimon Slavin, doctors have improved the science of training donor lymphocytes in a laboratory to act as honing devices to kill cancer cells, before being infused into a patient whose own lymphocytes are not properly doing their job.

The treatment, currently available only at Hadassah, is based on the use of lymphocytes taken from any donor, whether or not the patient’s and donor’s tissues match. Through a laboratory treatment, these cells are turned into ‘cancer killers’. After transfusion, these cells seek out and destroy any of the patient’s remaining cancer cells that survived previous anti-cancer therapies. This treatment is carried out in the Day Care Center of the Bone Marrow Transplantation Department at Hadassah, on an outpatient basis.

The therapy of using lymphocytes as the sole anti-cancer tool was first pioneered successfully by Slavin more than 18 years ago, and today it is used widely by all hospitals around the world.

For patients who have had bone marrow transplantation, Donor Lymphocyte Infusions (DLI) once had limited success rates. The activated donor cells were sometimes rejected as foreign bodies, and at other times were destroying healthy cells in addition to cancer cells, putting the patient’s life at risk. This is because lymphocytes are made up of both NK – natural killer cells, which are harmless and only target tumors – and T Cells, which can kill tumors and the patient, especially when mismatched donors are used for transplantation.

Hadassah is the first medical and research center to separate NK cells from T Cells, and to safely infuse the desired NK cells. The procedure uses mismatched cells that are maximally activated in a laboratory with recombinant interleukin 2, a commercially-available biologic product generated through genetic engineering, which is produced in the body in only minimal levels.

Interleukin 2 is what stimulates the lymphocytes to act as killers against cancer cells. When infused into the patient who originally received the donor’s stem cells, such cells may survive long enough to eradicate residual cancer cells that escape other therapies, causing relapse.

Twelve terminally ill cancer patients signed on for the experimental treatment in the past year and a half since it was developed. Of them, all of whom had tried every other available treatment and were told they had little time left, five are alive.

“It’s fantastic because they all were expected to have been dead long ago,” Slavin told ISRAEL21c. “When the laboratory-treated and separated NK cells are infused into a patient, they go immediately to work because they were already trained in the laboratory to become professional killer cells capable of recognizing and destroying foreign cells.”

Activated donor lymphocytes are also being used for patients who have such cancers as breast, ovarian, or colorectal cancer. In this second type of cell therapy, a non-related donor’s transplanted immune-system cells – activated with human interleukin 2, or activated against patients own tumor cells in the laboratory, when such are available – have been extremely successful in killing every last cancer cell in the patients. The theory is the same, in that the cells are trained to act as honing devices.

A Turkish woman, who was extremely ill due to very advanced and fully resistant blood cancer was one of the first to try the experimental infusion of activated mismatched NK cells 18 months ago, is back at work in Turkey with a fully clean bill of health.

Previously the treated cells were only generally infused intravenously to the blood but now can be infused directly to the site of disease.

“For patients with liver metastases, for example, we can infuse activated lymphocytes directly to liver, through the blood vessels that flow through the growing tumor, and provide higher, hence more effective concentrations of anti-cancer effector cells,” said Slavin.

The new procedure has little or no side effects, is done during fifteen-minute outpatient intravenous infusion and has already showed promising results in high risk patients with metastatic or resistant cancer.

Such treatments, like every procedure based on immunotherapy, would have been even more successful if patients undertook them at earlier stages of the disease, said Slavin.

“People use chemotherapy, which is occasionally hazardous, impairs the quality of their life and is not too effective against metastatic cancer. When a patient has already received optimal conventional treatment, surgical removal in the case of solid tumors, or maximal chemotherapy in hematological malignancies, and is known to have residual disease or is at high risk of relapse, it makes no sense to continue and treat such patients with additional conventional chemotherapy which will harm the patient but not kill ‘the last’ tumor cell,” he said.

“Then when the number of tumor cells is so small the chance of an alternative treatment with cell-mediated immunotherapy, especially mismatched and activated donor lymphocytes, is excellent. The reason I am optimistic is because we use mother nature’s tool – immune-system-cells to fight off disease. Normally too, it is the immune system that can recognize cancer cells as undesirable, and under normal circumstances, it will go on an attack until the single abnormal cell, which can grow to a bitter enemy, is gone. In patients with cancer, the patient’s own immune system failed to recognize the enemy and this is why we use the immune system cells from another individual that can easily recognize and destroy such tumor cells escaping the attention of patient’s immune system,” said Slavin.

Hadassah has also developed an experimental cell therapy in the form of a vaccine, which uses inactivated tumor cells originally obtained from foreign cancer patients with the same disease.

“Since we always immunize patients against a disease using the disease itself, for example tetanus against tetanus, attenuated polio against polio, attenuated influenza against influenza, there is no reason not to use a similar strategy against cancer,” said Slavin. To date, the vaccine has being used to treat patients with breast, lung, colorectal, and sarcoma and malignant melanoma.

Getting recognition for new therapies can take years. Despite early successes, all these cell therapies are prohibitively expensive and are not covered by the Israeli health funds or Israel’s National Insurance basket of medical services.

Though the therapy of using lymphocytes as the sole anti-cancer tool was first pioneered successfully by Slavin more than 18 years ago, it took ten years to become recognized by the Ministry of Health as an approved treatment. The recognition process of any new procedure creates a catch-22 for doctors and patients: In order for the procedure to be government-approved, a much larger number of patients must successfully undergo treatment.

But because the new cell therapies cost $8,000-24,000 a round of treatment, only few patients who could benefit if treated at the stage of minimal residual disease can afford them.

Slavin has kicked in large sums of money from his personal research fund, he says, to help some of the first-round patients, but won’t be able to continue treating patients unless additional funding comes in, either from insurance or from private or government sources.

He has also applied to patent the safer version donor lymphocyte infusion, as well as seeking and receiving some patents for advances made in the donor cell therapy to non-transplant patients.

Born in Tel Aviv 63 years ago, Slavin studied medicine at the Hebrew University-Hadassah Medical School, and specialized in internal medicine. He was especially interested in the then-young field of clinical and experimental immunology.He attended Stanford to study clinical immunology, rheumatology, immunobiology and experimental transplantation, and then to the Fred Hutchinson Cancer Research Center at the University of Seattle to study clinical bone marrow transplantation.

In 1981 he established Hadassah’s department of bone marrow transplantation, the Cancer Immunotherapy & Immunobiology Research Center and the country’s National Bone Marrow Transplantation Center.

Thanks to Slavin’s devotion to finding non-aggressive ways to treat cancer and the number of day-care treatments and patients which continues to rise, Hadassah recently inaugurated a new outpatient clinic to accommodate the changing needs of immunotherapy for patients with life threatening malignant and non-malignant diseases.