A virus that causes interstitial pneumonia — but even worse — can cause lethal systemic inflammation and a “Cell Factory” that produces stem cells that become drugs: can “Mesenchymal Stem Cell” become an effective therapy in combating COVID-19?

We discuss this with Dr. Giuseppe Astori, Head of the Advanced Cell Therapy Laboratory at Vicenza Hospital, and a member of the U.O.C. of Hematology.

Dr. Astori is one of the few people in Italy at the top of what is defined as a “Cell Factory” (there are only about ten in Italy), a Laboratory where human cells are studied and processed, in order to become drugs. His role is also “Qualified Person”, which in the pharmaceutical field means that he is the only person authorized by the Italian Medicines Agency (AIFA) to release a drug.

Dr. Astori, please describe for us how your Laboratory works.

The so called “Cell Factories” are organized as small pharmaceutical companies, only that the drug has the characteristic of not being of chemical or biotechnological derivation but is actually a cell. They’re called Advanced Therapy Medicinal Products (ATMPs). The cells are manipulated in a sterile and controlled environment, their quality is then ensured, and finally they’re stored at very low temperatures until they’re finally used.

AIFA carries out periodic checks of our work and authorizes us to release cells as experimental drugs (i.e. entering Phase I/II clinical trials). This process is the responsibility of the public structure, and therefore without any commercial interest. If the Phase I/II clinical trial is successful, the drug-cell could then be managed by a pharmaceutical company, able to take the clinical trial to the most advanced stages and then to its possible commercialization. This is the case for CAR-T cells that are revolutionizing the way we treat Leukemia and Lymphomas.

What therapy have you developed against the Coronavirus and what effect has it had?

We have to begin with the fact that the Advanced Cell Therapy Laboratory studies and treats mesenchymal stem cells which are cells normally responsible for the formation of bone, cartilage and adipose (i.e. fatty) tissue. They also have a very interesting characteristic: a strong anti-inflammatory capacity. They’re used, for example, in the treatment of Crohn’s disease or Graft-versus-Host Disease (GvHD) following allogeneic hematopoietic stem cell transplantation, where they succeed in blocking the proliferation of activated lymphocytes and consequently inflammation. Another very important feature of mesenchymal stem cells is that they can also be used between non-blood relatives without any danger of rejection, as they’re not recognized as foreign by the recipient organism.

We isolate and expand these cells directly from umbilical cord tissue, which would otherwise be waste tissue. The patient (or their family) donates the tissue to the tissue bank and from there it arrives at the Cell Factory. It takes a month of processing: from a few starting cells we get about a billion in total.

From where does your inspiration come and how does it relate to AIFA?

The idea of using mesenchymal stem cells on our patients comes from a series of coincidences. It was known that they had already been used in the treatment of pneumonia, not caused by SARS-CoV-2. In February of this year, a Chinese study had demonstrated the efficacy of these cells in a limited number of patients admitted to intensive care, back at the beginning of the pandemic.

At the same time, Dr. Marco Ruggeri, Head of our Hematology Department, and Dr. Rachele Ciccocioppo of the Gastroenterology Unit of the Integrated University Hospital of Verona, came up with the idea of trying to combine their respective expertise. We had the cells produced by our “Cell Factory” and the clinical expertise to do so. We knew that AIFA allows the cells to be used on individual patients with life-threatening conditions; it’s said in jargon, for “non-repetitive” use; once we had the approval of the Ethics Committee and AIFA we started the project. Dr. Monica Santimaria provided additional support to us from our Nuclear Medicine department, as far as the regulatory path is concerned.

Since it was now clear that SARS-CoV-2 (in severe cases) led to very extensive inflammation, there was hope that mesenchymal stem cells would have some therapeutic efficacy. Dr. Ciccocioppo made two infusions seven days later on a patient admitted to the Intensive Care Unit in Verona, observing a drastic reduction in inflammation, an improvement in respiratory parameters, coagulation and renal function.

How do you intend to continue, now that you’ve demonstrated the effectiveness of the treatment?

We’re planning a Phase I/II controlled clinical trial, led by Dr. Massimo Dominici of the University of Modena and Reggio Emilia. The trial will involve five “Cell Factories” and several Italian Clinical Centers. It’s a very ambitious project.

One very interesting thing is that, unlike other drugs that act on a specific pro-inflammatory cytokine, mesenchymal stem cells also have a potential regenerative capacity on tissues. So, one could think that the recovery of lung damage could be accelerated with great benefit for both patients and hospital facilities.

There’s a lot about stem cells; can you clarify what differences there are with the mesenchymal stem cells you used?

Unfortunately, after the “Stamina Therapy” case, there’s been a loss of confidence by many and also a lot of confusion in the use of the term “stem cells”. Generally, the term “stem cells” is used to refer to hematopoietic stem cells, which have the ability to regenerate blood cells.

We study mesenchymal stem cells that come from solid tissue and do not generate blood. In fact, we use umbilical cord tissue. In addition, we’re a specialized Laboratory and are subject to many controls that aim to ensure the safety of the cell at all stages of its use. I’d like to reiterate that cell-based treatments can only be carried out after obtaining authorization from AIFA and the Istituto Superiore di Sanità during authorized and controlled clinical trials.

What future do you envisage for the use of stem cells, and which types of stem cells are the most promising?

Cell therapies in general (of which stem cells are a part) have demonstrated both efficacy and safety, so I foresee that they’ll be used increasingly across the therapeutic field. Moreover, I think that in order to overcome current logistical problems, Cell Factories will have to become closer to hospitals, in order to bring the research aspect closer to the clinical aspect — and to accelerate the experimentation of drug-cells.

Is it also possible to think about using such a therapy for other problems?

As far as our Laboratory is concerned, we’re focused on the use of mesenchymal stem cells in Graft-versus-Host Disease (GvHD), in COVID-19 pneumonia, but we’re also looking at a possible therapy for Crohn’s disease. In collaboration with the group of Dr. Antonio Rosato, from the Istituto Oncologico Veneto, we’re also developing a protocol of immunotherapy, based on cells called Cytokine-Induced Killer cells (CIK) — appropriately redirected to recognize and destroy Leukemia and Lymphoma cells. We’re also involved in a project for the regeneration of the esophagus, through the use of mesenchymal stem cells and special “scaffolds” on which the cells grow.

In short, we collaborate with hospitals, universities and companies. The “Cell Factory” is the instrument through which the idea of a researcher is transformed into a therapy for a patient.

I’d also like to conclude by thanking the management of my hospital that has always believed in us and my group: there are six professionals (biologists, biotechnologists, pharmacologists) who have decided to focus on this sector. They have not stopped (not even for one day) during the COVID-19 emergency. Without them, nothing would be possible.

This post is also available in: Italiano

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