CAR-T therapy: the last bullet against the most resistant Hodgkin lymphomas

Between laboratories full of test tubes and oncology consultations full of patients at the Sant Pau Hospital in Barcelona, ​​the last bullet has been fired against some types of lymphomas refractory to all treatments: CAR-T30, a new experimental therapy that, in studies preliminary studies, has shown the first signs of efficacy against Hodgkin's lymphomas that do not respond to conventional drugs.

The therapy follows the technique of other CAR-Ts, which extract T cells from patients to improve them in the laboratory and re-inject them into the body so that they better recognize and kill cancer cells.

The CAR-T30, designed and developed entirely at Sant Pau, has been tested on 10 patients in a phase I trial to demonstrate its safety, but it has also given the first signs of efficacy:

half of the patients have had a complete remission.

It remains to be seen, however, if this disappearance of the tumor is consolidated over time and if the results are replicated in new trials with more patients.

This initial study has not yet been published in any scientific journal, but they have been presented at the European Congress of Hematology this week.

Hodgkin's lymphoma affects, according to the Spanish Society of Medical Oncology, three out of every 100,000 people;

that is, each year some 1,400 new cases are detected in Spain.

It is one of the most frequent haematological neoplasms, explains Dr. Javier Briones, director of the Cellular Immunotherapy and Gene Therapy Research Group of the Sant Pau Hospital Research Institute (IIB-Sant Pau): "It is one of the most curable lymphomas and there are many types of treatment: chemotherapy, bone marrow transplant, and other types of immunotherapies.

But there are between 20% and 30% of patients who do not respond to any treatment and have no therapeutic alternative.

And they are young patients, with an average of 30 years”.

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For them, for all those patients with tumors resistant to the conventional therapeutic arsenal, CAR-T therapies are making their way as a new strategy to annihilate these complex neoplasms.

This type of gene therapy, which extracts a type of white blood cells from the patient and reprograms them in the laboratory with genetic engineering to return them reinforced to the body and to recognize and kill tumor cells, has already been marketed for other types of hematological tumors, such as acute lymphoblastic leukemia or multiple myeloma.

Sant Pau's therapeutic strategy is, in essence, similar to those marketed, but has nuances and peculiarities to fine-tune the attack on Hodgkin's lymphoma tumor cells.

The CAR-T of Sant Pau is designed to give "weapons", in the words of Briones, to a specific type of T lymphocytes so that they recognize a protein -CD30- that is on the surface of the tumor cells of this type of lymphoma .

“The therapeutic target to which this CAR-T is directed is different from that of those that are marketed.

This targets the CD30 molecule, which is expressed in 100% of Hodgkin's lymphomas.

This protein gives life to the tumor, helps it to proliferate”.

The other CAR-Ts that are on the market are directed against other proteins, such as CD19.

Of all the types of lymphocytes there are, the Sant Pau CAR-T focuses on one of them: the memory T lymphocytes, "because they are the ones with the greatest antitumor capacity," explains Briones: "We take the patient's T cells and we enrich them, we give them a weapon so that they recognize those molecules [CD30] that are in the tumor cells”.

They identify them and kill them.

CAR-T30 cell culture seen under a microscope.

/ SANT PAU HOSPITAL

Phase I studies are designed to verify the safety of a therapy, but the first results already show efficacy results that, yes, will have to be verified with more studies, Briones clarifies.

Half of the patients made a complete response, which means that the disease has disappeared.

At least for now: they have been following the different patients for between one year and seven months, but it will be necessary to see if this remission persists over time or the tumor reappears.

The rest of the patients in the trial have had a partial response: the burden of disease has decreased, but tumor cells remain present.

“In CAR-T, when you don't have a complete response, the disease progresses.

CAR-Ts are very good, but they are not miraculous: we can induce a complete response, and even cure some patients,

A study therapy

There is a way to go.

The phase I study is only the first step and, although the phase II trial is already underway, we must wait to see if the results are maintained.

For now, there is no marketed CAR-T therapy against CD30 for Hodgkin's lymphoma, although there are two other large trials underway in the United States, Briones points out.

For Manel Juan, head of the Immunology Service at Hospital Clínic and one of the architects of the first academic CAR-T approved in Spain, this first study "is good news because a product has been developed that will be useful" in a group of patients , but it is necessary to demonstrate it in a more contrasted way and publish the results in a scientific journal, he adds.

José María Moraleda, coordinator of Advanced Therapies at the Carlos III Health Institute, agrees: "It is a first step that allows us to have hope, but it needs to be followed up."

In any case, he assures him, it is a "very important advance" achieved by the Sant Pau researchers: "It is a cutting-edge technology, from a Spanish group and to treat patients who do not have therapeutic alternatives.

It is a very substantial advance because, when you go to a second or third line of treatment and the prognosis is very dark, a treatment that has a 50% response is excellent news.

We are talking about the fact that there is a percentage of these people that can be cured”.

Moraleda also explains that there is little investigation of CAR-T for Hodgkin's lymphoma because it is a disease that responds very well to chemotherapy, but warns that "those that go wrong are very difficult to cure."

The doctor, who is also head of the Hematology service at the Virgen de la Arrixaca in Murcia and a member of the Spanish Society of Hematology, values ​​the fact that the Sant Pau CAR-T is aimed at memory T lymphocytes because, he assures , are lymphocytes that “naturally survive longer and it is a very intelligent choice” for the therapy to take effect.

Cheaper

Moraleda also celebrates the development of this academic CAR-T which, unlike those marketed by pharmaceutical companies, is cheaper and more accessible.

The Barcelona Clinic also developed two, one for acute lymphoblastic leukemia and the other for multiple myeloma.

“A medication of 300,000 euros is left at 50,000.

And the commercial CAR-Ts, while they are being prepared, take a month and some patients do not arrive.

You can have the academic in two weeks”.

According to the latest report from the Ministry of Health on advanced therapies, from a year ago, as of March 31, 2021, nearly 500 requests had been made for the treatment of patients with CAR-T.

The vast majority (375) were for diffuse large B-cell lymphoma and nearly a hundred were for acute lymphoblastic leukemia.

In recent months, however, the number of centers that use this gene therapy has increased and, predictably, the number of patients will also increase.

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