“The Italian government has decided to invest 60 million euros on CAR-T therapies, 10 million for each of the 6 pharmaceutical workshops”.

This was stated by Health Minister Roberto Speranza, explaining to the joint committees of the Senate and the House the program lines of his department.

CAR-T cell therapy consists of genetic manipulation of the cells of the immune system to make them able to detect and effectively fight cancer cells.

In particular, “CAR-T cells” are the patient’s “genetically educated” lymphocytes that seek, recognize and eliminate leukemia or lymphoma cells, from which the patient is affected.

A very expensive therapy that today, after a long wait, is also available in Italy in the form of a drug produced abroad by Novartis, but which in theory would be possible to produce and supply nationally.

It is one of the biggest challenges for our national health system, given that in the coming years the therapy could extend to a significant number of patients. But it is a challenge that Italy risks losing, also renouncing the positive effects on employment and development, if the “Italian way to Car-T” does not materialize with coherent and relative strategic choices investments.

We talked about it with Franco Locatelli, director of the Department of Onco-Hematology and Cellular and Gene Therapy of the Bambino Gesù pediatric hospital, one of the pioneers worldwide of this form of immunotherapy.

Locatelli, chosen by former Minister Giulia Grillo as head of the Higher Health Council, was appointed scientific coordinator of the Italy Car-T cells Project, an initiative commissioned by the Italian Parliament to “implement national research on advanced cellular therapies”. It is to him that we must refer to understand the potential of this therapy and realize the stakes at various levels, from the health of people to that of public accounts.

Professor Locatelli, you are one of the pioneers in Italy on clinical trials on Car-T cells. Briefly explain to us what this therapy is and why it is so promising.

“Car-T cells are an extremely advanced form of immunotherapy and can be considered a true model of personalized medicine, as well as precision medicine, thanks to the specific action on a precise molecular target. They are represented by T lymphocytes taken from the patient and subsequently engineered through a gene that codes for a Car (chimeric antigenic receptor, from the English chimeric antigen receptor), a receptor protein that makes them able to bind to the target molecule expressed on the tumor cell . Once the malignant cell is tied, the Car induces the activation of the toxic arsenal of the T lymphocyte, which, finally, determines the death of the tumor cell. Car-T cells have the prerogative of having to be specially prepared for each individual patient and to be used only for it. The advantages of immunotherapy with Car-T cells compared to the use of monoclonal antibodies include the ability to also eliminate tumor cells that express a low density of target molecule, the ability to proliferate and self-amplify upon activation and a better tissue distribution and infiltration. Furthermore, Car-T cells are so-called “live” therapies in that they are characterized by the possibility of entering the pool of memory cells that, over time, provide better long-term protection against disease relapses. Thanks to this technology and to the specific attack of Car-T cells towards a molecule called CD19, extraordinary results have been obtained in terms of response to treatment in patients, pediatric and young adults, affected by acute lymphoblastic leukemia with refractory B-cell precursors / relapsed and in adult patients with large B-cell lymphomas who had failed at least two conventional treatment lines “.

The two currently approved drugs are intended for patients with acute B-cell lymphoblastic leukemia or large cell lymphoma B. In what other cancers is the Car-T approach promising?”

The therapy with Car-T cells has the opportunity to breakthrough therapeutical options of numerous hematological conditions, but certainly there is the opportunity, or even the necessity, to better understand and define the mechanisms that regulate the efficacy or the possible toxicity associated with the use of this form of immunotherapy, as well as of develop this therapeutic approach even for patients with solid tumors. In particular, studies in the phase of realization / conclusion are showing an efficacy of the approach even in the context of multiple myeloma (in this case the antigen attacked by Car-T cells is the B-Cell Maturation Antigen, BCMA) and of Leukemia Chronic Lymphatic “.

In recent months there has been much talk of “an Italian way to Car-T”. What exactly is meant? That a drug will be developed as a result of Italian research or that Novartis and Gilead drugs will be produced in Italy, in dedicated public facilities?

“The understanding of what has been called” an Italian way to the Car-T “is to put together all the scientific expertise that exists in our country in this specific area, developing a series of pre-clinical projects to pursue. in a concerted and collaborative manner, aimed at achieving the following objectives: i) to identify methodological approaches able to obtain CAR cells in optimized times with contained costs; ii) improve the safety profile of Car-T cells, as well as their therapeutic efficacy; iii) extend the use of Car-T cells to solid tumors (where several factors can reduce the effectiveness of the therapeutic approach); iv) to define more precisely the mechanisms that govern the persistence of Car-T cells and, therefore, of the related therapeutic effect.As for production, one cannot hide a regret regarding the observation that commercially available Car-T cells are not produced on Italian sites, but, on the contrary, only in foreign sites. It is a missed opportunity to create high-tech jobs in Italian structures, giving employment opportunities to young biologists and biotechnologists trained in our country ”.

How much money has the Italian government invested in Car-T? How many do you think are necessary in the coming years to concretely implement the Italian road to Car-T?

“The appropriation that was dedicated to the development of an Italian consortium involving all the centers with qualification or interest for Car-T cells is equal to 5 million euros for each of the two years of the duration of the project. Thanks to this funding it will be possible to achieve the aforementioned preclinical objectives, and then, subsequently, to start clinical trial phases on the patient “.

In some documents of the Ministry of Health we talk about creating six centers of excellence for the research and production of Car-T. Recently, however, at the workshop on Car-T in Milan, there was talk of 20 structures. Tell us how this network should work.

“We need to clarify and distinguish what pertains to the identification and accreditation of Centers that will be able to administer the Car-T cells currently commercially approved, compared, instead, to the problem inherent in the creation of Italian production sites, in which the Car cells -T are prepared and validated for their clinical use. The first, that is the Treatment Centers, will certainly be more than the manufacturing sites, also to give a rational basis of sustainability with respect to the whole program. The process of identification and accreditation both of the treatment centers and of those appointed for the preparation of Car-T cells has been and still is the subject of careful evaluation by the Ministry of Health and the Regional Departments “.

Until a few months ago we read stories of patients who went abroad for treatment, gathering hundreds of thousands of euros on the web. Now finally the Aifa has given the green light to the reimbursement for Kymriah. Does this mean that Italian patients can already receive the drug even outside of experimental protocols or compassionate use?

“The approval by the Italian Drug Agency makes it possible today to provide therapy with commercially available products through well-defined pathways for the generation of specific Car-T cells for each individual patient. These requests can be formulated by the Centers that have obtained accreditation from the individual Regions. While in the past one could understand the emotional motivations behind these “journeys of hope”, today there is no reason to justify solutions like those described. In fact, in our country, there are both academic clinical studies (think as a paradigmatic example to the one active at the Bambino Gesù Hospital in Rome that I coordinate), and ways of using Car-T cells commercially approved, which make possible the treatments of patients who really have indications and can usefully benefit from them. It is obvious that it is unthinkable to use these therapies which, however, need longer observation times to fully establish their efficacy and safety in newly diagnosed patients, just as it would make no sense to want to employ Car-T cells therapy in patients that due to too advanced disease or poor general conditions they have no significant chance of benefiting from therapy”.

In a recent article in the New Yorker, the Pulitzer Prize and oncologist Siddhartha Mukherjee raises two important observations. The first is how correct it is to equate the Car-T (and in general the cell / gene therapy products) with common drugs. According to him, they should be treated as a different case and considered more similar to a medical intervention / procedure, with significant repercussions on patentability and costs. How do you see it?

“That Car-T cells are not a traditionally understood drug is obvious. The production chain itself is quite peculiar, starting in a hospital with the collection of the patient’s lymphocytes to be genetically modified with the Car constructs in special and authorized facilities called Pharmaceutical Workshops, whether they have a commercial connotation, rather than an academic value. Once prepared and validated for clinical use, Car-T cells then return to the hospital to be delivered to the patient for whom they were prepared “.

In the second point Mukherjee – looking further ahead, to a future in which this therapeutic approach could extend to other tumors, thus widening the pool of patients to be treated – questions which limits are imposed by the economic sustainability and the concrete feasibility of this therapy . Do you also believe that there may be a problem in this regard? What could be the solutions?

“It is indisputable that an extension of the use of Car-T cells to solid neoplasms would pose the problem of economic sustainability on the carpet, in particular for a country whose citizens are lucky enough to be able to benefit from a solidarity health system that covers all expenses. One account is to take on the costs of a therapy applicable to about 600 patients per year (these are the estimates available for the current indications approved by regulatory agencies, both for adult and pediatric patients) and another is that of having to guarantee the economic sustainability for an application that becomes massively wider. While emphasizing the complexity of the treatment and the need to prepare the cells specifically for each individual patient, it certainly cannot be thought that a Health System like ours is able to guarantee, without significant problems, a treatment extended to thousands of patients with the current cost of delivering Car-T cells. It is clear, therefore, that all solutions capable of reducing the costs related to the use of Car-T cells will have to be explored to guarantee access to all patients who in the future had the indication to be treated with this approach “.

There are so many researchers around the world who are working to understand how to improve Car-T. What are the most promising innovations?

“What we have achieved so far is only the beginning of the application development of Car-T therapy. The greatest efforts are concentrated on the extension of this therapeutic modality in the ambit of other hematological diseases and solid neoplasms. Then there is the interesting approach of simultaneously attacking two molecular targets through the so-called bispecific Car-T cells and the idea of trying to assess whether it is possible to create universal Car cells using other types of effector elements of our immune system, such as Natural Killer cells. In this last area, we have recently concluded a study being published in a prestigious journal that demonstrates a marked efficacy of Car-Natural Killer cells and their lower ability to produce inflammatory cytokines responsible for the development of toxicity related to these therapies “.

A critical aspect is the toxicity (5% mortality) and the search for predictive biomarkers of response or toxicity, and how to manage the toxicity itself. Tell us about the side effects of these therapies and how research is addressing the problem.

“Although effective, therapy with Car-T cells is not devoid of potential side effects, even life-threatening or even fatal. In particular, the two most relevant and peculiar complications of treatment are cytokine release syndrome and neurotoxicity. Cytokine release syndrome is associated with activation and in vivo expansion of Car-T cells at recognition of the tumor antigen. In the most serious forms, invasive support and the use of therapies such as corticosteroid drugs and monoclonal antibodies that block the action of one of the cytokines involved in the development of this condition, namely interleukin 6, are required. Neurological events associated with Car-T treatment occurs over the first few weeks of therapy and has been found, with varying incidences, in published studies. These events may have variable clinical manifestations, such as temporal-spatial disorientation, delirium, focal deficits, aphasia or convulsions. Generally the picture of neurotoxicity is self-limiting, but deaths due to cerebral edema not responsive to the treatments undertaken have been reported. The knowledge of the etiopathogenesis of the clinical picture of neurotoxicity remains limited to today and represents one of the most investigated areas to improve the safety profile of Car-T cells “.


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