Joan Gel, a 67-year-old man from Mataró (Barcelona), told this newspaper last December how he had saved his life thanks to innovative cancer treatments. Gel suffered for the last 12 years from multiple myeloma, a type of blood tumor, for which he was treated at the Hospital Clínic in Barcelona with an experimental therapy along with 30 other patients who had run out of options. Blood was taken from all of them to obtain their T lymphocytes (a type of cell that defends us from all kinds of threats such as infections or tumors) and to modify them with genetic engineering. It was intended to improve their own white blood cells so that they would be able to recognize the cancer cells that caused myeloma. Of these patients, 18 (60%) experienced a complete, although not necessarily indefinite, remission of the disease.
Great innovations are not usually confused with science fiction when they finally reach the sick, but these types of treatments, known as CAR-T (chimeric antigen receptor T-cells), would have seemed so a few decades ago. Carl June, a scientist at the University of Pennsylvania and one of the pioneers in this type of therapy, began thinking about making it a reality after his wife was diagnosed with ovarian cancer in 1996. A few days ago, June presented, together with several collaborators an article in the magazine Nature with the result of a decade-long follow-up of two of his first patients, Bill Ludwig and Doug Olson, treated for the first time in 2010. Despite reluctance to use the word when talking about cancer, the doctor considered them cured.
The work of the last two decades by a multitude of research groups, first in the US and later in other countries, has turned these previously experimental therapies into an opportunity for more and more patients. The experimental treatment that saved the lives of Ludwig and Olson became in 2017 the first CAR-T approved for commercial use in the US and later in Spain. Developed by the pharmaceutical company Novartis, today is known as Kymriah.
At the moment, like many cancer treatments in their infancy, they are showing their usefulness, especially in blood tumors, such as leukemia or lymphoma, and mainly in people who have already exhausted other therapeutic options. This happened with chemotherapies or targeted therapies that are now applied massively and as the first option in all types of tumors. In Spain, since 2019, less than 500 CAR-T treatments have been approved, a tiny figure given the more than 270,000 tumors diagnosed annually. However, the success of these early years means that they are already looking to expand their use.
Joaquín Martínez, head of the Hematological Tumors Clinical Research Unit at the CNIO-Hospital 12 de Octubre in Madrid, who has participated in international studies to expand the indications for these products, explains that one of the steps to extend their use “is to advance the moment it is applied, because the lymphocytes are healthier and the results will be better”.
In addition, it is sought that CAR-T also work in solid tumors, such as those of the colon or breast, which are much more frequent but also much more complex from the genetic or biological point of view. “In total, between 40% and 60% of hematological tumors, perhaps not in the first line, but at some point, may receive this type of therapy,” says Felipe Prosper, director of the Cell Therapy Area of the University Clinic. of Navarre. “They will have a high consumption in these rare diseases, but if we were able to transfer it to solid tumors, the numbers would be much higher and complex to manage,” he adds.
Prosper refers to a problem common to many of the most successful advanced therapies in modern medicine, with CAR-T leading the way.
So much Kymriah of Novartis as Yesletter Gilead, the two therapies of this type approved in Spain for commercial use, have a cost of more than 300,000 euros per patient. But even those developed by the hospitals themselves, such as the aforementioned Hospital Clínic, are close to 100,000 euros per treatment, due, among other things, to the fact that their creation is somewhat artisanal and requires staff with very specific training. The scientific and technological, but also political and administrative challenges that lie ahead are considerable.
“Between 40% and 60% of hematological tumors, at some point, will be able to receive this type of therapy”
Felipe Prosper, director of the Cellular Therapy Area of the Navarra University Clinic
According latest report data of the Advanced Therapies Approach Plan published by the Ministry of Health in June 2021, of the 497 requests for treatment with CAR-T since they arrived in Spain in 2019, 435 have been approved, almost 90%. However, only 244 of the patients who got the go-ahead received the therapy. In a type of patients who are usually already very ill, the time in which the process takes place, both administrative and technical, can mean the difference between life and death and that is another of the spaces in which the experts see room for improvement. “Now, in Spain, from the time the treatment is approved until the cells are reintroduced, it takes around 60 days. Reducing that time is very important, because with CAR-Ts, time has a very significant impact on the subsequent response,” says Martínez.
To ensure that innovative drugs do not involve such a high cost for the health system, the Government has negotiated a system of shared risks with pharmaceutical companies, through which the total price of the product is only paid if certain results are achieved. In addition, some experts point out that other cancer treatments can cost more than 100,000 euros per patient. The cost is a clear challenge to expand innovative therapies, but doctors believe that it is essential to value them for what they contribute.
From Gilead, one of the two pharmaceutical companies that market CAR-T in Spain, the hematologist Regina Quiroga, its medical director of cell therapy, highlights successes such as those recently presented by her company at the last congress of the American Society of Hematology. “In diffuse large B-cell lymphoma, in patients who previously had a life expectancy of 6 months, we have now seen that almost 50% [el 42,6%] they’re alive,” he says. Now, in his opinion, it is time to bring treatments like these to previous lines of treatment and to be applied in more hospitals. Until now, only nine in Spain can do it.
Quiroga does not venture to anticipate technological developments planned in companies like his to lower costs and make these therapies more affordable, but there are groups around the world that are working in that direction. Prosper says that with his team he is looking for alternatives to the genetic engineering necessary to modify T lymphocytes. Now, viruses are used as a means to transport the necessary modifications to the interior of cells so that they attack tumors. The team at the University Clinic of Navarra wants to change this vehicle for transposons, DNA sequences that are naturally capable of changing their place in the genome and that, produced synthetically, are used to introduce genetic sequences into lymphocytes to make them capable of attacking tumor cells. According to Prosper, this technology, if proven effective, can improve the security profile and make the process cheaper.
Among the future work on these cell therapies and other similar ones, increasing the safety profile while increasing potency and advancing towards its application in solid tumors also plays a fundamental role. “There are few targets for CAR-T that allow you to create a cell therapy that attacks the tumor and does not damage healthy tissue. Toxicities are a limitation”, points out Alena Gros, head of the Immunotherapy and Tumor Immunology Group at the Vall d’Hebron Institute of Oncology, in Barcelona.
In 2011, Emily Whitehead, a six-year-old girl with leukemia, relapsed after 16 months of chemotherapy and was one of the first people to receive CAR-T. So her immune system response came close to killing her, but she was able to be controlled with tocilizumab, a monoclonal antibody then used for arthritis. If Emily’s case had ended badly, as it did in some of the early attempts at gene therapy, the CAR-T field could have stagnated for at least ten years.
This control of toxicities will be key to the success of the jump to solid tumors. At VHIO, Gros and his team work with TILs (tumor-infiltrating lymphocytes), a technique with similarities to CAR-Ts. “We extract the T lymphocytes that have infiltrated a tumor and we screen to see which ones better recognize the tumor or certain mutations,” he explains. Then, those specially trained cancer-fighting cells multiply and are infused back into the patient. “It is a treatment that is still experimental, but it has interesting results in melanoma and in some cases of breast cancer,” he concludes. This technique, created by the surgeon from the US National Cancer Institute, another of the CAR-T pioneers, has shown spectacular results, like that of Judy Perkins. In 2014, this American woman had metastatic breast cancer and doctors did not give her more than two months to live. She is still alive today.
Gros and other doctors at the forefront of this revolution in cancer treatment believe it is important that patients “know that these options exist”, although they also warn that this is just beginning and the spectacular results such as those of Perkins, Ludwig and Olson are still exceptional. But the history of the fight against cancer gives reason for hope. In the sixties, an important part of the medical community considered it an aberration to treat cancer patients with chemotherapy. In the 1970s, with the first treatments available, more than 50% of children diagnosed with blood tumors survived and today the survival rate five years after diagnosis exceeds 80%. Many of these children, protagonists of that first revolution in oncology, are the best witnesses to its success.
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