The immunologist Paolo Dellabona
“The messenger RNA vaccines have worked against Covid-19, now this weapon is aimed at cancer. 40 international studies are in clinical phase 1 and 2, and there is already a tumor showing an effective response, melanoma. I say this in a low voice, but the feeling is that we are very close to a turning point “. The immunologist Paolo Dellabona, director of the Immunology, transplantation and infectious diseases division of the Irccs San Raffaele in Milan, has lived for decades in the laboratories: Turin, Lausanne, Strasbourg, then Milan. He answers questions as his gaze is captured by the 3D images coming to him from the slides of an 8K resolution microscope. They are gadgets with very refined technology – as well as very expensive – which seem to give him many confirmations in recent months.
Did you expect this ease in the “change of course” of vaccines?
I would have been surprised otherwise. Vaccination platforms based on messenger RNA are born for purposes other than Covid-19. Moderna was created to use RNA on genetic diseases, BioNTech to study cancer vaccines: co-founders, spouses of Turkish origin Ugur Sahin and Ozlem Tureci are famous researchers in cancer immunology. Being, that of RNA, a ductile and malleable platform, in a few months it was adapted to the Sars-CoV-2 virus.
Are there already results?
Yes, different. In addition to good experimental tests on melanoma, BioNTech has found that by modifying the structure of RNA, it can not only activate but also inhibit the immune response. And this possibility could serve, for example, after a transplant, to offer more tolerance with respect to rejection, blocking those autoimmune responses that are generated in the patient. In short, we could trigger an immune response but also inhibit it. These are unexpected opportunities even up to 4 or 5 years ago.
What are the goals of cancer vaccines?
The mRnas are directed for now against tumors for which immunotherapy, activated with monoclonal antibodies, has worked. The idea is not to use vaccines alone but to use them in a complementary way to support the immune response and increase the percentage of patients who benefit from them.
How many patients benefit from monoclonal antibodies today?
In percentage, up to 30-40% of cancer patients, it depends on the tumor.
What if an effective vaccine is added?
With the vaccine one can imagine pushing this response to 70-80%.
For which cancers?
Melanoma, as mentioned, but also lung cancer, head and neck tumors, triple negative breast cancer, which is very aggressive and shows interesting responses to antibodies. These are long studies but they will lead to improved therapeutic success.
Are they just hopes or is there more?
The efficacy and potency of these vaccines are already palpable in infectious diseases. So I’m more of a hope. The primary use of RNA drugs is with vaccines, but use can be broadened.
Meaning what?
Another immunotherapy approach, this time cellular, is based on the famous Car-T (a therapy that takes the cells of the patient with cancer, reengineering them in the laboratory to enable them to kill the tumor, ed), used for hematological tumors. The idea is: instead of making a genetically stable modification, it is thought to make a modification in a transitory way, using m-Rna and attenuating the toxicity of Car-T.
Is such a treatment conceivable also in solid tumors?
The latest research shows that it is also effective in solid tumors. However, an increasingly complex genetic manipulation of T lymphocytes (a type of white blood cell active in the immune response, ed) is needed.
Am I wrong or do T cells always give us surprises?
T lymphocytes have been studied for almost a century, we have very refined molecular knowledge. But we continue to discover new things about these cells, especially their adaptability in various physiological and pathological situations.
What other innovations emerge from the BioNTech forge?
They are trying to inject messenger RNA directly into the tumor site to produce immunostimulatory molecules. The latter unlock the immune system and trigger a virtuous cascade cycle, making the tumor susceptible to the response of RNA vaccines and immunotherapy with antibodies. Another possibility is to convey with mRna the production of antibodies that activate the immune system. Instead of injecting the antibody in the form of a protein, it is injected into the messenger RNA that produces that same antibody. It all lies in knowing how to measure the duration and location of drug production. The messenger RNA allows you to do this.
Will the victory over cancer arise from the combination of multiple therapies?
Let’s take melanoma, which is one of the cancers now covered by a number of effective therapeutic lines. Which are based largely on immunotherapy but also on pharmacological therapies with specific inhibitors. Immunotherapy acts from the outside, the new inhibitors directly on the tumor: the combination of these two approaches leads to therapeutic success. And so today most patients with melanoma have an extremely important long-term therapeutic perspective, they can live with a chronic disease. Deadly cancers are metastatic, not primary, which can largely be eliminated by surgery. The problem is to cure the metastases. It is difficult to cure them but the new approaches combined, with a strong immunological basis, are giving long and very long term survival prospects.
Can the melanoma strategy be used for other cancers?
I would say for all cancers treated with monoclonal antibodies: non-small cell lung cancer, head and neck cancers, urinary tract cancers, but in general they are being tested for all cancers. Furthermore, for the first time a cross-sectional immunotherapy has been approved for tumors that have particular genomic alterations, which represent 10% of the total. It is another crucial step forward for medicine.
And for those who don’t respond to immunotherapy?
In the other cases, the combination of the same immunotherapy with chemo and radiotherapy, and also with vaccines, is being tested. The idea is to go now on all cancers by striking with combination therapies. This is a huge chapter, which affects world research. There are more than 1,000 clinical trials in progress, which will even be difficult to analyze. Some studies are showing promising solutions. It is a long and expensive path that we must not interrupt, even considering the many failures that will occur, as always happens before the great discoveries.
What will these studies lead to?
All this work, for which we at San Raffaele are at the forefront, is leading us to understand why, by administering the same drug, one patient responds and another does not. We want to adapt personalized therapies to the genetic and genomic characteristics of each patient. Today we are much closer to knowing how to treat each patient with the right combination of drugs.
What role does Italy play in these studies?
We are a leading nation in the field of cancer immunology and immunotherapy. I mention two of the founding fathers of these disciplines: Giorgio Parmiani, who recently passed away, and Guido Forni. Both have uncovered fundamental immunological mechanisms. Teaching the world. To continue doing this, it is necessary to support research and development, and to do it with more conviction, because the high potential of our country does not correspond to what we are developing.