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Prostate cancer, what is the role of immunotherapy?

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Prostate cancer, what is the role of immunotherapy?

It is the most common cancer in men: every year there are 2.6 million new cases of prostate cancer in Europe and about 36,000 in Italy, with 6,800 deaths. However, survival is among the highest: 92% at 5 years, thanks to hormone therapy, chemotherapy, radiotherapy and surgery. But when the cancer is advanced or metastatic, traditional treatments could do little. And in these cases, immunotherapy does not help, unlike what happens with lung cancer or melanoma. But for what reason?

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A “cold” tumor

“We have known for many years that prostate cancer, such as breast or pancreatic cancer, and hormone-sensitive cancers in general, create immunosuppressive microenvironments around them, ‘cold’ from an immunological point of view,” he explains. Oncoline Licia Rivoltini, oncologist and head of the human cancer immunotherapy unit at the IRCCS National Cancer Institute Foundation in Milan. That is, elements accumulate there, such as macrophages or myeloid cells for example, which activate a negative regulatory mechanism of the immune system. In other words – explains the oncologist – environments that turn off the immune response, that inhibit it, eventually protecting the tumor and not the patient. “We can therefore imagine prostate cancer as a sort of immunological sanctuary, which keeps away the T lymphocytes, that is the cells that guard and start our defense mechanism when there is something foreign inside us, such as a virus or a bacterium and, in fact, a tumor “.

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But it is not just a question of the microenvironment: it is not just the context that makes prostate cancer insensitive to the immune system and to the immunotherapeutic drugs that stimulate it. Prostate cancer, in fact, is characterized by DNA mutations that make cancer cells little recognizable by the immune system, unlike mutations associated with lung cancer or melanoma. “All this – continues the expert – means that the disease is currently difficult to deal with with the immune checkpoint inhibitors PD1, PDL1 and CDL4, or with the immunotherapy drugs available today”.

The exception

However, there is a small percentage of patients, about 5%, who respond to immunotherapy and benefit from it. They are the carriers of the MRI mutation (or microsatellite instability) and patients whose tumors have a high burden of tumor DNA mutations (Tumor Mutation Burden or TMB). These genetic alterations make the cancer cell recognizable by the immune system. “It has been seen that for this small subset of patients, after other therapies such as hormone therapy and chemo have failed, immunotherapy can extend survival. It should be emphasized that we are talking about a strategy not yet approved and administered in the context of clinical trials ”, says Rivoltini.

Making cancer more attackable

Several studies are underway, at European and national level, in which attempts are made to counter the immunosuppressive effect of the tumor microenvironment with already known drugs. The idea is to make the tumor more immunologically attackable and, with combined immunotherapy, to stimulate the immune system to attack it. We are talking about a combination of oncological drugs such as, for example, PARP inhibitors which, as some studies have highlighted, act on the tumor microenvironment making it more accessible to the entry of elements of the immune system, and of check point inhibitors, which they enhance its activity.

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Cancer vaccines: where are we?

In 2013, three years after the US, sipuleucel-T was approved in Europe as a cellular immunotherapy for hormone-resistant metastatic prostate cancer. It was the first approval of a therapeutic vaccine for cancer (anti-cancer vaccines are therapeutic, not prophylactic: that is, they do not make us avoid the disease but are a cure). Simplifying, the cellular technique works like this: from a blood sample from a patient some particular white blood cells are isolated and engineered in the laboratory to express the prostatic acid phosphatase or PAP protein, which is the same protein that is expressed by cancer cells on their surface. Once modified, these cells are re-injected into the same patient from which they were taken, where they teach the T lymphocytes how to attack the cells that produce PAP, those of cancer, in fact. But sipuleucel-T has never been used on this side of the ocean: “Sipuleucel-T was the pioneer of cancer vaccines, and has proven effective in actually extending survival by a few months in patients who used it, but the difficulty of large-scale production here in Europe, and also the very high costs at the time, meant that this method was not successful in Europe ”.

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However, the concept of cancer vaccines continues to be interesting. “Today we are more mature and able to accept therapies of this type, also thanks to the techniques for obtaining CAR-T cells, which we now produce in Europe, and to the Covid effect that has cleared the very idea of ​​a vaccine. We are also more used to cancer treatments that are much more expensive than those. An anti-cancer vaccine should be used in combination with a checkpoint inhibitor, because we know that the immune response tends to die out ”concludes Rivoltini:“ We believe that the road to the so-called anticancer vaccines is still open. Much depends on the commitment of the industry and also on the political strength of patient groups ”.

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