Joan Gel, a 67-year-old resident of Mataró, Barcelona, told EL PAÍS last December how his life had been saved by innovative cancer treatments. Gel had suffered from multiple myeloma, a type of blood tumor, for 12 years and had been treated with experimental therapies at the Hospital Clínic in Barcelona along with 30 other patients who had run out of conventional options. Blood was taken from all of the patients to obtain their T-lymphocytes – a type of cell that defends the body against various threats, including infections and tumors – to modify them through genetic engineering. The goal was to improve their own white blood cells so that they would be able to recognize the cancer cells responsible for myeloma. Of the patients, 18 of them (60% of the total) experienced complete, if not necessarily indefinite, remission of the disease.
Great medical innovations tend not to be mistaken for science fiction when they finally reach patients, but this type of treatment, known as CAR-Ts (T cells with chimeric receptors for antigens) seemed certainly have been around for decades. Carl June, a University of Pennsylvania scientist and one of the pioneers of this type of therapy, began to believe it might become a reality after his wife was diagnosed with ovarian cancer in 1996. Earlier this month, June and several co-authors published an article in Nature with the results of a decade-long follow-up of two of her first patients, Bill Ludwig and Doug Olson, who were first treated in 2010. Despite her reluctance to use the word when discussing cancer, June considered them cured.
Over the past two decades, the work of several investigative teams, first in the United States and then in other countries, has transformed what were once experimental therapies into a real chance for ever more patients. The treatment that saved Ludwig and Olson’s life in 2017 has become the first CAR-T approved for commercial use in the United States. Developed by pharmaceutical giant Novartis, today it is known as Kymriah.
At present, like many cancer treatments in their early stages, it is proving useful mainly against blood tumors like leukemias and lymphomas, and mainly in patients for whom all other therapies have been exhausted. This happened before with chemotherapy and targeted treatments which are now widely used as the main option against all kinds of tumors. Since 2019 in Spain, less than 500 CAR-T treatments have been approved, a drop in the ocean compared to the 270,000 tumors diagnosed each year. However, the success of this treatment in its early years led to calls to expand its use.
Joaquín Martínez, head of the hematological malignancies research unit at the 12 de Octubre hospital in Madrid, which has participated in international studies aimed at expanding the indications for these products, explains that one of the steps towards expanding the use of CAR-T is to “advance when it is applied because the lymphocytes are healthier and the results will be better.
In addition, it is hoped that CAR-Ts will also act against solid tumors, such as those of the colon or breasts, which are much more frequent but also much more complicated to treat from a genetic or biological point of view. “In total, between 40% and 60% of hematological tumors, perhaps not at an early stage, but at some point, could receive this type of therapy”, explains Felipe Prósper, head of the advanced therapies unit and unit co-director. Hematology and Hemotherapy Unit of the University of Navarre. “They will have strong uptake in these minority diseases, but if we could transfer it to solid tumors the numbers would be much higher and difficult to manage.”
What Prósper is referring to is a common problem among many of modern medicine’s most successful advanced therapies, of which CAR-T is at the forefront.
Reducing the time between when the treatment is approved and when the cells are reintroduced is very important, because with CAR-T, time has a very important impact on the subsequent response
Joaquín Martínez, Head of the Malignant Hematological Research Unit at 12 de Octubre Hospital
Kymriah treatments, along with Yescarta from biopharmaceutical company Gilead, have been approved in Spain and cost around €300,000 ($340,000) per patient. But even CAR-Ts developed in hospitals, like the one at Hospital Clínic in Barcelona, can cost more than €100,000 ($113,000) per treatment, among many other reasons, because creating them requires an almost artisanal touch. and highly and very specific training. staff. The scientific and technological challenges awaiting us, as well as political and financial ones, are considerable.
According to data from the latest report on the Spanish Ministry of Health’s Advanced Therapies Approach Plan, dated June 2021, of the 497 CAR-T treatment requests that have been made since arriving in the country in 2019, 435 approved: nearly 90%. However, only 244 of the patients who received the approval actually received the treatment. In a group of patients who tend to be very ill already, the time it takes to complete the process – both in terms of administration and technical issues – can mean the difference between life and death. This is another area that experts say can be improved. “Today in Spain, between the moment the treatment is approved and the moment the cells are reintroduced, it takes around 60 days. It is very important to reduce this time scale, because with CAR-T, time has a very important impact on the subsequent response,” explains Martínez.
To try to ensure that innovative medicines do not represent a prohibitive cost for the public health system, the Spanish government has negotiated a risk-sharing system with pharmaceutical companies, through which the full price of the product will only be paid that if it is predetermined the results are obtained. Additionally, some experts note that other cancer treatments can cost more than $100,000 per patient. The financial aspect presents an obvious challenge to expanding the availability of these therapies, but doctors believe it is essential to recognize their intrinsic value.
Regina Quiroga, medical director of cell therapy at Gilead, talks about success stories like the one her company recently presented at the American Society of Hematology meeting. “In diffuse large B-cell lymphoma, in patients who previously had a life expectancy of six months, we now find that almost 50% [42.6%] are alive,” says Quiroga. Now, she adds, it’s time to align such treatments with previous ones so that they can be applied in more hospitals.
Quiroga doesn’t go so far as to suggest advancing technological developments being developed in companies to reduce costs and make these therapies more accessible, but there are groups around the world working along these lines. Prósper says he and his team are looking for alternatives to the genetic engineering needed to modify T-cells. As it stands, viruses are being used as a way to carry the necessary modifications into cells to attack tumors. The team from the University of Navarre wishes to substitute this method for transposons, known as “jumping genes”, which are DNA sequences naturally capable of changing place in the genome, and which could be used to introduce sequences into lymphocytes. to allow them to attack tumor cells. According to Prósper, this technology, if proven effective, could improve the safety profile of the process and make it cheaper.
Improving the safety profile at the same time as increasing the potency are key elements of future work on this type of cell therapy and other similar treatments in the perspective of being able to apply them to solid tumors. “There are few targets for CAR-Ts that allow the creation of a cell therapy that attacks the tumor without damaging healthy tissue. The toxicities are a limitation,” says Alena Gros, head of the immunotherapy and immunology department at the Vall d’Hebron Institute of Oncology in Barcelona.
Between 40% and 60% of hematological tumors, perhaps not at an early stage, but at some point, could receive this type of therapy
Felipe Prósper, co-director of the Hematology and Hemotherapy Unit at the University of Navarre
In 2011, Emily Whitehead, a six-year-old girl with leukemia, had a relapse after 16 months of chemotherapy. She was one of the first people to receive the CAR-T treatment. At the time, her immune system response was on the verge of killing her, but tocilizumab, a monoclonal antibody used for arthritis, managed to control it. Had Emily’s case gone awry, as has happened with some of the earliest attempts to apply gene therapies to such cases, it could have set CAR-T treatments back at least 10 years.
This control of toxicities will be a key element in the success of the leap towards solid tumors. At the Vall d’Hebron Institute, Gros and his team work with TILs (tumor infiltrating lymphocytes), a technique with similarities to CAR-T. “We remove the T cells that have infiltrated the tumor and screen them to see which best recognize the tumor or any mutation,” she says. These cells, which are particularly useful in the fight against cancer, are multiplied and reintroduced into the patient. “It’s still an experimental treatment, but it has shown interesting results in melanoma and in some cases of breast cancer,” adds Gros. This technique, developed by surgeons from the US National Cancer Institute, another CAR-T pioneer, has given spectacular results, as in the case of Judy Perkins. In 2014, Perkins was diagnosed with metastasized breast cancer and doctors gave her two months to live. Today, she is still alive.
Gros and other doctors at the forefront of this revolution in cancer treatment say it’s important that patients “know these options exist,” though they also warn of dramatic results like those of Perkins, Ludwig and Olson, pointing out that these therapies are still in their infancy. Yet the history of the fight against cancer gives reason for hope. In the 1960s, much of the medical community considered chemotherapy treatment an aberration. 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 is over 80%. Many of these children, who participated in the first oncological revolution, are today the greatest testimony to its success.