There is a disease, the acute lymphoblastic leukemia, which is prevalent among children. In this blood tumor, a particular type of immune system cells proliferates uncontrollably and accumulates in the blood, bone marrow and other organs. The term “acute” indicates the rapid progression of the disease. Until recently, it was a disease without hope of cure, while in the United States the approval was given for the first time to a therapy that finally aspires to cure this disease: produced by the pharmaceutical company Novartis, it is called Kymriah and it is the most expensive therapy in the world ($ 475,000 for a single administration).

To understand more, we interviewed Dr. Attilio Bondanza (we had already heard about an important award given to him and his team, see here), a former researcher at the Vita-Salute San Raffaele University, transplantologist and Principal Investigator of the “Innovative Immunotherapy” Unit.

Dr. Bondanza, first of all, why this name, “Kymriah”?

In the biomedical field there is not always a real motivation behind the choice of a name: in the case of Kymriah there is no relevance between the “biological” name and the commercial name of the drug. It is very likely that he was chosen from a shortlist of other candidates, usually catchy, curious or particular.


What is Kymriah?

It is a therapy, to date approved only in the United States, to treat acute lymphoblastic leukemia in children and young adults. This therapy is based on T lymphocytes – a subtype of white blood cells – modified to recognize and kill cancer cells. The immunotherapy of the tumor (that is to fight the tumor with the help of the immune system cells) is a powerful weapon against cancer, which today can support the “classic” surgeries, chemotherapy and radiotherapy. In Europe, however, the drug has reached the experimental phase 2 (a preliminary verification of therapeutic efficacy is being conducted) for acute lymphoblastic leukemia in the child.

What does this therapy consist of?

The therapy involves taking T cells from the patient’s peripheral blood, which are isolated and cultured in the laboratory for 7-10 days. The lymphocytes are treated with viral vectors, particular viruses deprived of their harmful component that contain a gene with the information to “teach” the cells to recognize the tumor. This technique is called “genetic engineering” and the lymphocytes thus modified are called CAR-T lymphocytes; they are then washed and infused again in the patient. Once in the patient these lymphocytes migrate to the tumor, multiply and kill it, behaving like real living drugs. The principle of Kymriah is that a single intravenous administration is enough without the need of subsequent “calls”, as CAR-T behave like serial killers: a few lymphocytes are infused that kill a first tumor cell, then they expand, then kill a second tumor cell, expand and so on, in a kind of chain reaction. They can be defined as “living drugs” because they expand and contract depending on the tumor burden they encounter. To date, CAR-T lymphocytes have already given surprising results in various blood cancers.


Is it a therapy also applicable to solid tumors?

At the moment it is not so simple; to selectively kill the tumor, the CAR-T lymphocytes must recognize a “flag” (called “antigen” in technical jargon) that identifies a tumor cell. The problem in solid tumors is that often the antigen expressed by the tumor cells is similarly expressed by perfectly healthy tissues, therefore the lymphocytes are deceived and also attack these harmless cells. Kymriah itself is in fact specific only for a certain type of leukemia, in which the tumor cells express a particular antigen called CD19. The “revolution” that has been talked about Kymriah is still to be demonstrated, even if the applicability of immunotherapy on solid tumors is a very interesting frontier and one of the strands of research that are conducted in our laboratory.

Dr. Bondanza with two collaborators of his team, Dr. Barbara Camisa (left) and Dr. Margherita Norelli (right). Photo: Marco Montagna
Dr. Bondanza with two collaborators of his team, Dr. Barbara Camisa (left) and Dr. Margherita Norelli (right). Photo: Marco Montagna

In the experiments conducted so far, we speak of tumor in remission in 83% of cases. What does this mean in a clinical sense? Is it a good result?

It is an exceptional result. In Europe even the patients recruited for the phase 2 study were patients (children and young adults) with a prognosis of a few months and refractory to any type of therapy, so having an 80-90% response is definitely an incredible result. Unfortunately, not everyone gets a response, because in many cases the tumor cells “hide” the CD19 on the surface, in order not to be recognized, so the CAR-T lymphocytes are no longer able to eliminate them.

What are the problems of Kymriah therapy today?

One is the fact that they spend 7/10 days from the patient’s withdrawal to the re-infusion of the cells; another is the use of viral vectors as a means of transferring the gene to the lymphocytes. Moreover, it is an individualized therapy, developed each time in an exclusive way on the cells of a single individual, and this certainly introduces the element of subjectivity. Each patient is different from another, so it is not always possible to generate the therapeutic product: for example, it is not possible to perform it in immunosuppressed patients, deprived of the immune system. The great challenge for the next future is to try to make this therapy a standard, industrially large-scale product, and to use other alternative tools to the viral vector as a gene transfer modality.

Why does it cost so much?

In our laboratory we calculated that the cost of the therapeutic product itself is around $ 100,000. To these you must add the costs of the viral vector, which can even reach $ 50,000. Adding up everything else, such as the costs of production, maintenance of the structures, the staff, we estimated that the final price would have been about $ 600,000; In comparison, $ 475,000 seems almost a reasonable cost! I understand that it can sound exaggerated: one of the objectives will certainly be to lower costs and production times.

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