Acute Lymphoblastic Leukemia (or ALA) is a blood cancer that affects approximately 400 children and adolescents each year in Italy. A life-changing tumor not only affects children but also their families.
We spoke about it with Dr. Giusseppe Gaipa, Director of the Laboratory of Cellular and Gene Therapy “Stefano Verri” Asst. Monza, San Gerardo Hospital and researcher at the Tettamanti Foundation.
Dr. Gaipa graduated in Biology from the State University of Milan, receiving a Doctorate in Experimental Oncohaematology. Since 1995, he’s worked at the Tettamanti Research Center in Monza, specializing in the study of leukemia in children.
CARCIK CELLS ARE T-CELLS WITH A NATURAL PROPENSITY TO FIGHT CANCER, WITH A VERY HIGH TOLERANCE TO HEALTHY TISSUE
Dr. Gaipa recently published an article on a new therapy for Acute Lymphoblastic Leukemia (Acute Lymphoblastic Leukemia or ALA) in “The Journal of Clinical Investigation” in which you have made a strong contribution, please explain to us what this is about.
It’s a Phase I/II study that aims at testing the safety, some aspect of efficacy, and the maximum tolerable dose of an advanced therapy drug. In this case, a CAR cell (Chimeric Antigen Receptor) that is used for immunotherapy.
The patients we’ve treated are patients with ALA precursor B (the disease originates from a B lymphocyte clone) who have already undergone a course of therapy, including a bone marrow transplant, which however, did not yield positive results; they are said to have suffered a relapse.
Why is it important to study and find a cure for ALA?
In the pediatric field, today ALA affects about 400 children every year in Italy, and approximately 60 children are treated at the Tettamanti Foundation each year. ALA is treated with chemotherapy protocols and finally, where necessary, with transplantation. Unfortunately, about 15% of sick children relapse, and in this case, the disease becomes very aggressive. Our work is directed towards the development of new, more effective and less toxic treatments to be integrated with those currently in use — with the ambitious final goal of achieving 100% treatment.
How do CARCIK cells differ from CAR-T cells?
There are several advantages. Let’s try to list them in their most important points:
- CAR-T cells are engineered cells derived from T lymphocytes taken from the patient through leukocytopheresis. In our case, instead, we started from lymphocytes of the bone marrow donor, so we’re specifically talking about an allogeneic source. In the case of recurrence, we ask the donor to make a simple donation of only 50 milliliters of peripheral blood, and we engineer these cells to produce the CARCIK, which is to be injected into the sick patient.
- CARCIK cells are T cells with a natural propensity to fight cancer but also display a very high tolerance to healthy tissue. These characteristics together identify them as an excellent candidate for immunotherapy.
- To engineer CARCIK we don’t use retroviral or lentiviral vectors as in CAR-T, but rather molecules called transposons that introduce the CAR sequence by electroporation (i.e. permeabilization of the cell membrane by electrical impulses) into the CIK cell. The introduction is random but very safe, as demonstrated by the safety tests conducted during the study and as required by the regulatory body that must authorize the continuation of the trial until the drug is marketed.
- Starting from peripheral blood, the retrieval of lymphocytes is much easier and more feasible than the leukocytopheresis required by the traditional CAR-T technique. Moreover, CARCIK are prepared directly by us in the cell factory: the Cell and Gene Therapy Laboratory “Stefano Verri”, which is accredited by AIFA.
- CAR-T cells can currently be used on leukemia patients in an age range from early childhood to 25 years old, due to the toxicity of the treatment beyond this age. CARCIK can also be used on patients well over 25 years of age.
It’s important to point out that the CARCIK project was born about 10 years ago and was coordinated from the beginning by Dr. Biondi who had the inspiration for the project and on which many of us have actively contributed, and in particular Dr. Chiara Magnani and Professor Ettore Biagi. Over the course of these past ten years there’s also been a massive transformation from laboratory research to the cell factory, so that the CARCIK has become a gene therapy drug.
Recently, the “Plagencell Project” was launched. What is the role of the Tettamanti Foundation in this project?
One of the objectives of the Plagencell project is to connect five cell factories in Lombardy: the Cell and Gene Therapy Laboratory “Stefano Verri” Asst. Monza with the Tettamanti Foundation, the Cell Therapy Laboratory “G. Lanzani of Asst. Papa Giovanni XXIII” in Bergamo, the Cell Factory of Fondazione IRCCS Policlinico San Matteo of Pavia, the Cell Factory of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan and the Cell Factory of Istituto Neurologico Besta in Milan. A partner in the project is also the IRCCS San Raffaele Hospital in Milan.
All these facilities will pool their tremendous skills and knowledge to develop cell and gene therapies against devastating diseases such as oncological, renal and neurodegenerative diseases. The project will be developed over three years, funded by a call for proposals established by the Regional Foundation for Biomedical Research (FRRB) of the Lombardy Region, and the San Gerardo Hospital of Monza, which has charged the aforementioned and Professor Biondi to coordinate its activities will coordinate the part of oncohaematology.
What is the goal of this project?
Within this oncohaematology project, our goal will be to expand the availability of CARCIK cells using a new source of lymphocytes (i.e. using umbilical cord blood instead of peripheral blood, alone). The great advantage lies in the fact that cord blood is deposited at public banks such as the bank of the Policlinico di Milano. In addition, the T lymphocytes contained in cord blood are less immunogenic; this means that there is less risk of rejection and more patients can be treated because the degree of donor-receiver compatibility is greatly increased. An additional advantage is that the preparation of CARCIK cells can be performed in advance, and consequently, time is gained in the treatment of the leukemic patient who often cannot afford to wait a long time.
The production of CARCIK from umbilical cord blood will then have to go through all pre-clinical validation studies; in particular, our colleague Sarah Tettamanti will take care of this, and clinical duties, as we’ve already done in the past for CARCIK cells from peripheral blood — in order to ensure the safety standards required by AIFA.
How did your passion for research in the oncohaematological field come about and what difficulties do you encounter during your daily work?
I’ve had a passion for research since the beginning of my studies, and it was encouraged by some teachers who made a big difference, because in addition to the notions they transmitted, there was the fascination of the demand and the complexity of nature. From then on, I’ve never left oncohaematology.
There are difficulties but I try to overcome them with the awareness that I’m not alone. Behind the doors of the laboratory, I know that there are young researchers who are experiencing the same difficulties as me and as head of a unit of the laboratory I have a duty to provide support, guidance and encouragement to them. This is very important because in the research work every time an answer is found, new questions are always raised.
In addition, entering the laboratory, I always pass through the atrium of the day hospital of the Maria Letizia Verga Center, in order to meet with the children who are waiting there to be received. I also meet the gazes of their parents who are living an experience that I have not lived, and that I can only imagine being the father of two boys with such a condition. Looks full of uncertainty, fear but also of hope. This motivates me very much to do my job in the best way possible.
What would you say to a young person who wants to pursue a career in scientific research?
Today, to undertake the profession of a researcher is perhaps more difficult, because the scenario has become a lot more competitive. A young person must have great enthusiasm, determination, curiosity and ambition in order to achieve their goals. Having experience abroad is fundamental to have more open-mindedness and cultural openness; always with the hope of being able to return to Italy and contribute to the development of scientific research in our country, which I consider a requirement for both social and cultural progress.
In thanking Dr. Gaipa we’d like to conclude by saying that treatments and cures, as in this case for ALA, are not arrived at by chance and even fewer are realized in a short time. They are the result of years of study, work, trial and error and, above all, of the vision of someone who, in sitting in front of a blank sheet of paper, sees a path that others do not see — and they begin to sketch it, and they’re supported by valid collaborators who work within teams — all towards the same goal.
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