ARI: Behind the First European-made CAR-T-Cell Therapy


In 2021, a hospital in Barcelona managed to get approval for the first European-developed CAR-T cell therapy. Aided by a little girl and her mother, a team of doctors at the Hospital Clinic Barcelona moved early to learn from the American physician that pioneered the treatments, did not take no for an answer, and is now treating leukemia patients.

Our original idea was simply to treat patients because we knew that CAR-T worked and that many of our patients would die in the six to seven years that it would take for the industry to bring therapies to the market.

Dr Manel Juan, Head of Immunology, Hospital Clinic Barcelona

The story begins with a girl called Ariana Benedé. The girl, known as Ari, was diagnosed with acute lymphoblastic leukemia and, after an intense fight, passed away on 2 September 2016. Prior to her passing, Ari and her mother Àngela inspired a crowdfunding movement that resulted in a breakthrough project, and one that would eventually spare the lives of cancer patients like Ari, the first European-made CAR-T-cell therapy.

CAR-T (Chimeric Antigen Receptor T-Cell) is a type of cell and gene therapy in which the patient becomes its own donor. It involves modifying a patient’s T-lymphocytes so that they are able to attack tumour cells.

The ARI project – which officially stands for Advanced Research Initiative but whose name was designed to honor the young Ariana – raised over EUR one million from companies, foundations, associations, and individuals, and was led by a group of doctors at the Hospital Clinic Barcelona.

Leading the team of doctors was Manel Juan, the current head of the Clinic’s Immunology Department. His personal involvement with CAR-T cells, and the roots of the ARI project, began more than a decade ago after learning that an American doctor, Carl June, had successfully treated patients with lymphocytic leukemia – the most prevalent cancer among children and adolescents in the United States, according to the CDC – using the technology in the United States. Losing little time, Dr Juan and his colleagues reached out to their counterparts and crossed the Atlantic to meet with the group led by Dr June at the University of Pennsylvania (UPenn). Collaboration was established. The objective was to introduce the revolutionary therapy to Spanish patients. But, soon enough, Big Pharma swooped in. Swiss giant Novartis signed an agreement with UPenn and opted to conduct development by themselves, declining the Clinic’s offer to treat patients in Barcelona.

Not taking no for an answer, Dr Juan and the team started exploring alternatives. “We were in contact with the Novartis team at the beginning, trying to include our center in their program, but they decided that it was not a priority at that moment,” he recalls. During a following call with Dr June, the Hospital Clinic Barcelona team made its case; sharing their two decades experience using dendritic cells (DCs) and T cells with the American pioneer, who in turn suggested they should be able to develop their own therapy. Following Dr June’s advice, the Clinic team started working to produce CAR-T cells. “In hindsight, it was the right decision because it took Novartis a long time to get a product approved,” Dr Juan told HCLS.

It did not take much for the Spanish doctors to understand why UPenn had chosen to collaborate with Novartis; development is an expensive undertaking – especially for a publicly funded hospital like the Clinic Barcelona. Fortunately, they were not alone, they were to meet Ari and her mother.

“Since we lacked the resources to move beyond the pre-clinical phase, the crowdfunding helped us move to clinical trials and prove that the therapy worked,” said Dr Juan. “Our original idea was simply to treat patients because we knew that CAR-T worked and that many of our patients would die in the six to seven years that it would take for the industry to bring therapies to the market. It might sound naive to some, but we wanted to make our findings openly available, sharing protocols just as it is done in other medical areas.”


Fractionating an historic approval

Early in 2021 – eleven years after Dr June successfully treated the first patients in the Pennsylvania – the Spanish Agency of Medicines and Medical Devices (AEMPS) approved ARI-0001 for patients with acute lymphoblastic leukaemia.

The clinical trial had demonstrated that the Clinic’s CAR-T produced a complete response – meaning that no residual disease remains – in more than 70 percent of patients.

“Our project started with the idea of conventional one-shot infusion first developed at UPenn,” recalls Dr Juan. “[But] after detecting problems in three patients, we decided to modify the protocols, with the blessing of the authorities, and found that side effects were extremely reduced in patients with fractionated doses.”

Fractionating the doses, he said, significantly reduces side effects, particularly cytokine storm syndrome – similar to the hyper-inflammation caused by COVID-19.

In fact, Dr Carl June himself had warned about cytokine release syndrome after detecting it in three patients early on. The patients, he said during a panel discussion in 2017, had 5-7 pounds of tumor each. “When their tumor got ablated by the CAR-T cells, it was violent. They had fevers which lasted – in one case – 2 weeks, until the tumor was all gone. The patients recovered and they were completely fine. There were no long-term side effects from that.”


The owners of health

Under the current rules, only a handful of big pharma companies have the opportunity to succeed. A situation that is made worse by some revolving doors between the regulator and industry …

Dr Manel Juan

Fractionating infusions might help reduce many side effects of CAR-T-cell therapies, but regulators must give the go ahead. “Unfortunately, we are not allowed to [fractionate infusions] because of the pharma rules. I believe that all patients, not only ours, would benefit but companies are not so interested, because under ordinary rules, it will require additional clinical trials,” Dr Juan laments. That is why – remembering that time Big Pharma opted to exclude them – the Clinic team decided to do something different. With the expectation that more hospitals could have the tools to follow suit, they made their findings openly available.

“If we accept that the system in place is good enough and that pharmaceutical companies alone should manage gene and cell therapies, then many patients with rare conditions, like paediatric or infrequent cancers, will be left out,” Dr Juan believes.

It is a realisation based on the few options currently available for non-industry institutions to create and provide CAR-T-cell therapies. The one chose by the Hospital Clinic Barcelona was the EMA’s Hospital Exemption (HE) rule which allows for unlicensed, developmental advanced therapy medicinal products (ATMPs) to be used to treat patients under certain conditions through a specific authorization. In other words, a one-time permit for a single institution.

“Under the current rules, only a handful of big pharma companies have the opportunity to succeed. A situation that is made worse by some revolving doors between the regulator and industry; it is quite a strange situation, at least for us looking to treat patients.”

Nevertheless, Dr Juan continues to see the pharma industry as an ally, albeit one to follow closely. “I do not believe that our work is opposed to that of pharma companies; they complement each other. We want to develop treatments because the industry should not be the owner of our health. They are one part of the health system. Public health systems must work for the people, not the other way around. There is a lot to be gained by finding alternative paths to innovative treatments.”

In the end, Dr Juan’s grassroots view of CAR-T-cell therapies reflects little Ari and her mother’s crowdfunding quest. The immunologist believes that all major hospitals in Spain have the basic capabilities to replicate their success, so long as they follow the right protocols. The Clinic team, and partners, are currently producing the therapy in Barcelona and Pamplona, at the Clínica Universidad de Navarra (CUN), for five centres: the Hospital Clinic Barcelona, the CUN, and three in Salamanca, Seville, and Murcia. “The next step is to help all involved centres conduct their own production,” asserts Dr Juan. And for Ari’s mother, Àngela, the new generation of personalised medicine should be a global tool against diseases, telling La Vanguardia that “We asked ourselves why, in this globalised world, we could not have access to a therapeutic possibility like this. We wanted it to be available to anyone as soon as possible.”

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