CAR-T therapies can cause secondary blood cancers

CAR-T therapy was one of the most important “revolutions” in cancer treatment of the last years. In particular, it has changed the prospects for patients with incurable blood cancers, who had not been able to obtain results with all the other treatments available and who can now recover and fully recover their lives. Patients who no longer had any hope, who had little left to live, can now (in some cases) consider themselves cured. The American drug agency (Fda, Food and drug administration), however, announced on November 28th that these therapies can cause secondary tumors and a few days ago the European agency (EMA, European medicines agency) also announced that it had started a review on the safety of CAR-Ts. What happens? How worried should patients who have already received this treatment be? Do any special checks need to be done? Many answers are already contained in an article, just published in the prestigious scientific journal Nature Medicine
by an international group of top specialists in the field, including Fabio Ciceri, director of both the Hematology and Bone Marrow Transplant Unit and the Cancer Center of the IRCCS San Raffaele Hospital in Milan.

Six CAR-Ts also used in Italy

There are six Car-T therapies approved in the EU and in Italy: tisagenlecleucel (Kymriah), lisocabtagene maraleucel (Breyanzi), axicabtagene ciloleucel (Yescarta), brexucabtagene autoleucel (Tecartus), idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti). «Currently in Italy CAR-Ts are authorized by Aifa (therefore reimbursed by the NHS) for patients with relapsed or refractory diffuse large B-cell lymphoma – explains Ciceri -; for pediatric and adult patients with Refractory B-cell acute lymphoblastic leukemia, in post-transplant relapse or in second or further relapse; For primary mediastinal large B-cell lymphoma; For Epstein-Barr virus-related large B-cell lymphoma relapsed or refractory to two or more lines of therapy. And we expect the green light for it shortly myeloma».

What are CAR-Ts

After the first test in 2012 on an American girl, today CAR-Ts are an opportunity for an ever-increasing number of patients. Thanks to the results obtained even in complex cases they have sparked great hopes, but it is a therapeutic option to be “handled with care”: side effects (which can be very serious, even lethal) are managed better and better, but highly qualified centers and personnel are needed. So that in Italy there are around 30 hospitals authorized to use them. The technique consists in taking, in a simple way, from the individual patient's blood his own T lymphocytesthe “soldiers” of our immune system appointed to defend us from diseases, who are no longer capable of fighting against the tumor, for strengthen them in the laboratory. With genetic engineering techniques it is induced in T lymphocytes (through the introduction of the CAR receptor, which stands for Chimeric antigen receptor) the ability to specifically recognize and kill cancer cells. Thus reworked and enhanced, the lymphocytes are reinfused into the patient and begin their battle against cancer. A fight that, if successful, could mean definitive healing.

23 cases of secondary tumors

Let's come to today. When the FDA announced the cases of secondary cancers at the end of November, it noted that pose a possible risk to all six approved CAR-Tsunderlining however: first, that it is about a very rare occurrence and, second, that for the sick the current benefits far outweigh the danger. During the annual meeting of the American Society for Hematology (ASH) held in December, some illustrated studies exposed some cases of secondary neoplasms, trying to give the first explanations. «After over ten years of use and with over 34,400 people treated worldwide to date have been registered 23 patients who, years after receiving CAR-Ts, developed secondary tumors – explains Ciceri -. These are, specifically, secondary malignancies related to T cells, including lymphoma and T-cell leukemia. There is no alarm: pharmacovigilance is a standard procedure for all medicines and consists of collection of side effects relating to products (therapies and vaccines) already authorized. So we can detect cases like these, study them and understand how to act accordingly.”

A danger already known

The EMA Pharmacovigilance Committee, which began a review a few days ago, recalled that secondary tumors were considered an important potential risk of CAR-Ts already at the time of their authorization and were included in risk management plans. What does it mean? «We already knew that the transfer of the CAR gene into T lymphocytes can cause a mutation in the lymphocytes themselves with their carcinogenic transformation. This eventuality, known as insertional mutagenesisis considered extremely rare and we still do not know what factors can lead to this complication, but careful clinical observation and specific biological analyzes will be able to answer its real incidence.” What should patients treated with CAR-T do? «Nothing, because they already carry out regular checks at the Centers where they received CAR-T therapy, as required by the normal management protocols of these treatments» concludes Ciceri.

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