From success to challenge: this is how the European approval of the first Spanish gene therapy against cancer was achieved

The CAR-T therapy (from the acronym T lymphocytes with a chimeric receptor against antigen, in English) developed by the Hospital Clínic de Barcelona-Idibaps, called CAR-T ARI-0001, for the treatment of acute lymphoblastic leukemia (ALL ) represents a double milestone for the centre, Catalan health and the whole of the National Health System.

On the one hand, it achieves a

who, after suffering the failure of other therapies, have no alternative;

and, on the other, it obtained in February 2022 the PRIME designation from the European Medicines Agency (EMA).

The latter means that this academic and public immunotherapy is a

, something so difficult to achieve that it is the first academic product to receive this designation.

For this reason, the Clínic team is

.

A year before that, in February 2021, this CAR-T therapy received approval as a non-industrially manufactured advanced therapy drug by the Spanish Agency for Medicines and Health Products (Aemps), with what

.

The approval in Spain is for its use in patients older than 25 years with ALL resistant to conventional treatments, a gap in the current indications of the industrial CAR-T marketed in Spain.

"Promote own and public manufacturing"

Authorized sources from the Ministry of Health have told this newspaper that "promoting the own and public manufacture of these medicines in the academic field of the SNS, in conditions that guarantee quality, safety and efficacy standards is

".

They recall that, on February 1, 2021, the AEMPS authorized the first non-industrially manufactured CAR-T;

its price was approved on May 17, and it

, "so that all patients could access it with guarantees of equity in

, regardless of the place where reside."

What does the therapy consist of and how did it get the green light?

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CAR-T ARI-0001 targets the CD19 antigen on tumor cells.

After extracting the patient's T lymphocytes by leukapheresis, they are genetically modified in the clean room of the hospital itself by inserting a gene that codes for the chimeric antigen receptor (CAR), with which its action against cancer cells is enhanced.

Then those modified cells are infused back into the patient.

For the structure of this receptor, the

that found this new application.

and for the genetic change, a virus is used as a vector, also produced in the Barcelona acute center.

To assess the efficacy of this CAR-T, a

, led by Julio Delgado, a hematologist at the Clínic, and Susana Rives, a hematologist at the Sant Joan de Déu Maternal and Child Hospital in Barcelona.

The trial results showed that there was a complete response in more than 70% of patients, meaning no residual disease remained.

And before that, preclinical studies have already shown that CART ARI-0001 was capable of controlling disease progression in animal models and that its efficacy was very similar to that of other available CAR-Ts.

Clinical

, while the same team develops CAR-T ARI-0002, which changes the target of tumor cells from CD19 to BCMA to treat patients with multiple myeloma, also resistant to other treatments.

This second CAR-T, in a clinical trial led by specialist Carlos Fernández, has already shown that, after one year of follow-up, 75% of patients are still alive and without disease progression.

This milestone, in the opinion of the ministry now in charge of Carolina Darias, "

and in its management, thus opening up a source of opportunities for the SNS. Previously, in order to regularize the conditions of use of non-industrially manufactured advanced therapy drugs in the SNS, on October 14, 2019, the agreement was approved in plenary session of the Interterritorial Council (CISNS) by which the general conditions of planning, coordination , contracting and acquisition of non-industrially manufactured advanced therapy drugs, whose ownership belongs to the publicly owned structures and services integrated into the SNS".

How will your production be scaled for Spain and Europe?

José María Moraleda directs the Spanish Cellular Therapy Network of the Carlos III Health Institute (TerCel), a collaborative project that began its activity under the first RETICs call of the Carlos III Health Institute in 2003 with the aim of promoting research in cell therapy and transfer scientific advances in this field to SNS patients.

It is made up of

, clinicians and medical professionals working together, under a multidisciplinary and cooperative approach, with the main objective of discovering and describing the mechanisms of the beneficial actions of cell therapy in human diseases by developing experimental approaches, including autologous and heterologous cell transplantation from different cell populations (adult, embryonic or IPSC), to improve the health of patients.

Moraleda informs this newspaper that the current one is the model of success that they have wanted to have: make preclinical models, clinical trials up to advanced phase II and

, so that it is in charge of large-scale development.

Among the most outstanding projects, he points out the CAR-T, of which he indicates that

.

In his group are all those who work with CAR-T in Spain.

Manuel Juan, head of the Immunology Service at the Barcelona Clinic.

For Moraleda, what they do "

, we have never seen their efficacy results before: patients with relapses before all available therapies are in complete remission. It had never been seen before".

Now they are destined for hamatological tumors, but Moraleda believes that the "real revolution" will come when they reach solid tumors.

Regarding the CAR-T of the Clínic de Barcelona,

, he points out that the key to it will be

who need them and guaranteeing the sustainability of the SNS.

From the national network, the objective is to join efforts to produce CAR-T

, because from a single hospital the therapy will not be able to scale: "

have to participate . The luck is that we have several since Bernat Soria's stage in the Ministry of Health (2007-2009), which opted for cell therapy, which generated great controversy as to whether the cells had to be embryonic or adult, but without that today there would not be up to 12 hospital clean rooms certified by the AEMPS, which range to be more and not only for the CAR-T".

Perhaps scaling it further, for Europe, requires a private company, "preferably Spanish," says Moraleda.

As

he sees: financing, from the outset;

the awareness of the importance by local managers, and "personalisms. Working in collaboration and sharing is difficult and, if the complexity of intercommunity relations is added, even more so".

In this context, she confirms that

".

With the impulse of a young patient

The Clínic's CAR-Ts bear the name ARI

, a young woman diagnosed with ALL who died on September 2, 2016. She and her mother, Àngela Jover, promoted the so-called "ARI Project", which gave an important boost to the development of the first anti-CD19 CAR-T therapy.

The

had, specifically, two lines of action: the investigation of the CAR-T of the Clinic and the improvement of home care for oncology and hematology patients.

Nearly 1.8 million euros were raised from companies, foundations, associations and individuals, in a movement based on a social proposal that was, without a doubt, fundamental.

The CAR-T ARI-0001 has been developed by a multidisciplinary team of more than 175 professionals also led by Manel Juan, head of the Immunology Service at the Center for Biomedical Diagnosis (CDB) of the Clinic and responsible for the joint platforms of the Maternal-Child Hospital Sant Joan de Déu.

He explains to this newspaper that, in addition to the clinical efficacy of the new therapy,

, and makes it possible to lower the cost of producing the therapy for make it affordable in academic institutions and available to all patients.

The evaluation carried out by the AEMPS of the CAR-T ARI-0001 has been carried out following the European regulatory standards and applying the Spanish legislation for non-industrially manufactured advanced therapies, which guarantee that the Clínic therapy meets the required quality criteria, safety and efficacy.

Juan especially highlights

, who, evaluating the option of going to the United States to participate in the clinical trial of a CAR-T, saw that the cost -one million dollars- was clearly limiting.

"We were in the process of being able to facilitate that same therapy and the young woman and her parents, knowing about it, designed a high school final project thought of how to contribute to achieving our goal," says Juan.

When he attended the concert that marked the beginning of the project, in which the group Love of Lesbian performed in the Luz de Gas room in Barcelona, ​​Juan thought that the girl's project could be successful, because

.

Unfortunately,

for another reason associated with his disease, without being able to benefit from the CAR-T that bears his name, but thanks to his initiative he managed to treat the first 10 patients with it: three adults and three children with ALL ;

three with lymphoma and one with chronic lymphoblastic leukemia.

Those 10 patients were not a sufficiently relevant sample and

adult ALL patients, which was the most complicated part (the industry had achieved this in those under 25 years of age).

In that situation, the Clínic team

in a meeting with the presence of the current Minister of Health of the Generalitat, Josep Maria Argimon, who was then manager of the Catalan Health Institute.

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