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The sanctioning of gene therapy as standard treatment will open up entirely new perspectives for patients with leukemia and lymphoma. Doctors hope that the solution that is effective in blood cancers can be adapted to the needs of patients with other types of cancer.
Research companies and universities are racing to develop these new therapies designed to remodel and turbo-charge millions of cells of the immune system in cancer patients, turning them into cancer killers, sometimes referred to as “living medicine”. One of the main research goals would be to include such treatment in patients with breast, prostate, ovarian, lung and pancreatic cancer.
“This method has proven to be most revolutionary in treating blood cancer,” said Dr. Stephan Grupp, director of the cancer immunotherapy program at the University of Philadelphia, professor of paediatrics at the University of Pennsylvania and head of major research in the field. – If it still works for solid tumors, it will be a revolution in oncology – says the expert. However, it takes at least five years to see if it works.
New therapy, new hope
This type of therapy is already being tested in the treatment of glioblastoma, an aggressive brain tumor recently diagnosed with Senator John McCain. The research results obtained by scientists from the University of Pennsylvania, published a week ago, did not provide a clear answer. Of the ten patients treated with this method, one has survived more than 18 months with what scientists have termed “stabilized”, two other patients live with progressive cancer, and the remainder have died.
However, research continues on many fronts. The researchers now intend to extend the experimental treatment to children in the earlier stages of leukemia, combining this method with others and developing completely new types of cell therapy.
The products that are closest to approval have a limited effect – they are intended only for the treatment of blood cancers such as leukemia and lymphoma, but not for tumors originating in organs such as the nipples and lungs, which are responsible for many more deaths. In the USA, about 80. people are being treated for blood cancers, which will be eligible for innovative therapy, with a total of 1,7 million of all cancers diagnosed annually.
The new therapies are likely to cost hundreds of thousands of dollars and come with high risks. Participants in earlier studies have died of treatment side effects, such as severe fever, low blood pressure, and pulmonary embolism. Doctors have learned to control these symptoms somehow, but experts remain concerned about possible long-term effects of treatment, which in theory could be secondary cancers caused by neutralized viruses used in genetic engineering. So far, such tumors have never developed, but it is too early to rule out the risk of them.
Genetic modification
New treatments for leukemia require the patient to take millions of leukocytes called T cells (sometimes also known as “immune system soldiers”) from the patient, genetically modify them to recognize and kill cancer cells, multiply them, and bring them back into the person’s bloodstream. This process is expensive as it has to be performed separately for each patient.
Solid tumors would be less amenable to treatment with these modified cells (called CAR-T by scientists), but many research centers are looking for gene therapy applications in the fight against mesothelioma, cancer of the ovaries, breast, prostate, pancreas and lungs. “These bumps are like Fort Knox,” admits Grupp. “They don’t want to be affected by T cells. For them, we need a combination of different methods: CAR-T cells and something else, but until we know what that would be, we won’t get the same results.
The pioneering T-cell therapy was established at the University of Pennsylvania, which has licensed Novartis to conduct research in this field. The American Food and Drug Administration has advocated the use of this method in a narrow group of seriously ill patients, of whom there would be only a few hundred per year in the US: these are people aged 3-25 years with recurrent acute lymphoblastic leukemia resistant to standard treatment. The prognosis for these patients is poor, yet clinical trials have shown that T-cell therapy has frequently led to long-term remission and sometimes even cure.
Novartis will later this year seek approval for treatment in adults with a specific type of lymphoma – relapsed, refractory B-cell lymphoma. Novartis’ competitor, Kite Pharma, also applied for the possibility of using gene therapy in lymphoma patients. Juno, on the other hand, failed in this field and ended the study after five participants died of swelling in the brain. Kite also recorded such a case. Novartis is looking for applications for other types of T cells, with various genetic enhancements, to treat chronic lymphocytic leukemia, multiple myeloma, and glioma.
A way to treat blood cancers
Promising results have been obtained with the improvement of existing gene therapies in blood cancer patients. Thus, patients with lymphoma were given T cells along with a drug called ibrutinib, and the combined treatment was more effective than using the two methods separately. The Children’s Hospital in Philadelphia lacks room for patients wishing to take advantage of this new option, who sometimes have to wait months for treatment, although many do not have that long. Waiting lists will shorten once treatment is officially approved and more widely available.
Grupp believes that a step in the right direction would be to apply gene therapy to patients at an earlier stage of the disease, rather than delaying this form of treatment until the last minute, as required by current legislation. The scientist reports that a study is planned in several medical centers involving children with early signs that standard and often effective chemotherapy is not working for them. It is hoped that clinical trials in these patients will start in the next six months. “We would have introduced this treatment much earlier, before [these children] became so ill,” the scientist promises. This would be another important step in research into the proper use of these cells.
According to Grupp, prior administration of the modified T cells would have allowed some patients to avoid bone marrow transplantation, an invasive last resort treatment. There are also studies on children combining the use of T lymphocytes with the administration of immune checkpoint inhibitors to increase the effectiveness of T cells in fighting cancer. Many studies are planned, but for Gruppa, “this is just the beginning”.
T lymphocytes from Novartis products and from previous therapies of its competitors, were modified in such a way as to search for and destroy cells with the CD19 surface marker – a characteristic protein in many leukemias and lymphomas. However, it would be useful to set other targets for T cells as well, since CD19 does not proliferate in leukemias, according to Grupp. In the next phase of research, known as “super important”, the modified cells would attack two different targets in the same patient. Next year, this approach would be applied to the treatment of children and adults with chronic myeloid leukemia, which the Grupp says is a “persistent disease”.
Therapy available immediately
Researchers at the MD Anderson Cancer Center at the University of Texas, Houston, are trying yet another approach in cell engineering to create an “out-of-the-box” therapy that would not need to be individually developed for each patient, and would therefore not be that expensive. Instead of using T lymphocytes, the team at this center is studying the potential of cells known as “natural killer” cells, NK cells of the immune system that fight anything they find foreign. Instead of taking material from a patient, researchers Katy Rezvani and Elizabeth Shpall obtain NK cells from cord blood donated by women just after the baby is born. Unlike T cells, which cannot be safely administered to a patient other than the person from whom they were collected, NK cells can be introduced into the body without fear of attacking the recipient’s tissues, sometimes triggering a disastrous rejection reaction. (…).
NK cells are genetically engineered to attack CD19 proteins and produce a substance that activates their action and helps them survive in the body. In addition, they have a ‘switch’, a gene that scientists can turn off if the treatment starts to cause dangerous and uncontrolled side effects.
After promising tests in mice, scientists decided to study adults with relapsed or refractory chronic lymphocytic leukemia, acute lymphocytic leukemia and non-Hodgkin’s lymphoma. The first patient had just started treatment, Rezvani reported.
One unit of cord blood provides enough material to treat five patients, and within two weeks the number of NK cells can be increased by 500-fold, to a billion. – We intend to create a product that will be given to the patient in its fresh form, but we are also working on optimizing the freezing process [of this drug] so that we can manufacture, freeze and store it for patients who will someday need it.
Also read: 10 steps in the fight against cancer