Cancer immunotherapy: a new weapon against cancer

Numerous clinical studies are demonstrating the great potential of immunotherapy, one of the most recent therapeutic options to treat some forms of cancer.

In the war against cancer, medical and scientific research has made it possible to develop new and increasingly effective and sophisticated weapons.

The most recent front of care, a real turning point, has been opened by researchers with immuno-oncology drugs, which have joined traditional therapies (chemotherapy, surgery, radiotherapy) and which counteract tumor pathology by stimulating the immune system. Immunotherapies, that is, reactivate the body’s defenses.

These are innovative molecules that are proving to have the potential to improve long-term survival and clinical outcome of several “difficult” malignancies such as melanoma and lung cancer. For other forms of cancer, which affect for example the breast or the brain, the experimentation is still in its infancy.

The critical aspect, at the moment, is the high costs for the health system and the length of time for citizens to have access to these medicines.

The numbers of cancer in Italy

Cancer diseases in our country, as in all industrialized countries, are widespread and represent one of the greatest health dangers, as well as one of the main causes of death.

Despite the progress of science and medicine in recent decades and the numerous prevention campaigns, in 2011 in Italy there were about 175,000 deaths (almost 99,000 among men and almost 77,000 among women), about three per thousand people.

The most frequent cancers, excluding skin cancers, are colorectal, breast and prostate cancers, followed by lung and bladder cancer.

“In 2014, more than 2.9 million Italians were diagnosed with cancer in their lifetime, with women showing a higher prevalence (56%) than men (44%),” explains Walter Ricciardi, president of the Higher Institute of Health.

And he adds: “As regards, instead, the incidence (ie new cases), the most updated estimates of the AIRTUM (Italian Association of Cancer Registries) report that every year about a thousand tumors are diagnosed per day, with an annual rate of about six cases per thousand people, higher in men (6.9 / 1,000 inhabitants / year) than in women (5.4 / 1,000 inhabitants / year). However, comparing the 1996 data with the most recent ones available, there is a significant decrease in mortality, of 18% among men and 10% among women.

Italy has a frequency of neoplasia and survival values similar to those of France, United States, Australia, Sweden, Norway, Finland, Denmark.

How the immune system works

The immune system is a collection of organs, cells and substances that help protect the body from infection and disease.

Any new substance that enters the body and is not recognized by the immune system triggers an alarm, causing a reaction of the system itself. It is therefore considered to be composed of two lines of defence:

• the innate one, which includes barriers such as the skin
• the adaptive one, which “reminds” immune cells of the invasion of a foreign organism and reacts quickly in a subsequent exposure.

The substances that provoke an immune response are called antigens: the immune response can destroy anything that contains an antigen, such as germs or the cancer cell. However, healthy and cancerous cells do not differentiate clearly and the immune system does not always recognize them as foreign.

How does immunotherapy work?

Immunotherapy is a therapeutic strategy that uses certain parts of the immune system to fight cancer, in two ways:

– stimulating the immune system to work harder or more intelligently to attack cancer cells

– providing the immune system with additional components to strengthen it.

So, unlike traditional cancer therapies (chemotherapy, radiotherapy, surgery), it does not act directly on cancer cells to destroy them, but pushes the immune system to do so.

The main types of immuno-oncology therapies include:

• monoclonal antibodies: these are particular versions of immune system proteins produced by humans and can be designed to attack a very specific part of the cancer cell
• Cancer vaccines: substances introduced to provoke an immune response against certain diseases
• Nonspecific immunotherapies: treatments that stimulate the immune system in a generic way and can thus help it attack cancer cells.

Very promising results

“The history of immunotherapy is not only recent – underlines Paolo Marchetti, director of the Department of Medical Oncology of the Sant’Andrea Hospital in Rome – but only in recent years have immunotherapeutic agents been developed that have shown, in the various clinical studies, to be able to contribute to “raising the bar” in the fight against tumors, especially with regard to the main objective of oncological therapies: the prolongation of long-term survival’.

«Melanoma – continues the expert – is one of the neoplasms in which the greatest number of trials with immunotherapies (ipilimumab, nivolumab and pembrolizumab) has been conducted in recent years, with important results both in overall survival and in terms of disease progression“.

And he adds: “Another neoplasm in which new treatment scenarios are opening up, with a significant improvement in survival rates, is non-small cell lung cancer. But immunotherapy is helping to improve the prospects for many other cancers, including kidney cancer and head and neck cancer, with promising results in studies comparing it to standard chemotherapies, which bode well for the future of the fight against cancer.

The advantages of immunotherapy

Immunotherapy has great potential for the treatment of different forms of solid (i.e. affecting tissues) and hematological (which cause abnormal proliferation of blood cells) tumors. “The advantages – continues Marchetti – derive from four factors in particular: the possibility of combining different agents (and therefore different mechanisms of action); the “immunological memory” that would contribute to the adaptability of the therapy and thus to improve long-term results; the unique safety profiles of these therapies, which reduce the risk of side effects; the fact of targeting not the tumor but the immune system, which would allow us to act against different tumors”.

“That’s why several immunotherapy agents are being studied for multiple types of cancer, with a gain from the point of view of survival for many neoplasms that until recently had decidedly more unfavorable prognoses than those they may have in a few years”.

The fight against melanoma

Melanoma is the cancer that has allowed us to obtain most of the knowledge currently available: the key element was the discovery of “checkpoint inhibitors”, molecules involved in the mechanisms that allow the tumor to escape the control of the immune system.

Immunotherapy is carried out with monoclonal antibodies that inhibit checkpoints (in a sense, “disarm the sentinels”) and reactivate the body’s anti-tumor immune response, chronicizing the disease.

Paolo Ascierto, director of the Melanoma Unit, oncological immunotherapy and innovative therapies of the Pascale National Cancer Institute, Naples, explains: “After laboratory experimentation, 2011 marks the starting point of immunotherapy in clinical practice with the approval of the first monoclonal antibody (ipilimumab) directed against CTLA-4 (cytotoxic T-lymphocyte-associated protein 4). Within a few years, several other immune checkpoint inhibitors were developed, such as pembrolizumab and nivolumab, which were approved by the Food & Drug Administration (FDA) and the European Medical Agency (EMA) for the treatment of patients with advanced melanoma.

A recent meta-analysis, which considered 4,846 patients treated with ipilimumab, showed that 20% of patients are still alive after ten years. Chronic disease has also been observed with nivolumab, both in melanoma and other cancers.”

Immunotherapy agents have a different toxicity profile than traditional therapies, due to the hyper-reactivity of the immune system (skin reactions, colitis/diarrhea, autoimmune hepatitis, endocrinopathies and pneumonia) but can generally be managed with corticosteroids.

Ascierto concludes: “Five years of immunotherapy in melanoma have taught us that checkpoint inhibitors help overcome the mechanisms by which tumors escape destruction by the immune system. Long-term survival can be achieved in groups of patients suffering from different solid tumors or hematological malignancies. Predictive biomarkers may help select patients most likely to benefit from immunotherapy, and various approaches are currently being evaluated.

Progress against lung cancer

Giorgio Vittorio Scagliotti, director of the Department of Oncology of the University of Turin, explains: “In the treatment of non-small cell lung cancer, anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies allow the patient’s immune system to identify and destroy cancer cells, through the activation of T lymphocytes”.

“The immunotherapies available are the anti-PD-1 nivolumab, approved in the United States and the European Union for non-small cell squamous lung cancer and in the United States for non-small cell non-squamous lung cancer, and pembrolizumab, approved in the United States for both forms and pending approval in the European Union. Two anti-PD-L1 antibodies, atezolizumab and durvalumab, and the anti-CTLA-4 antibody ipilimumab are also being studied. Clinical studies conducted so far show that monotherapy with immunotherapy drugs is able to improve both overall survival and progression-free survival, compared to standard chemotherapy.

Is immunotherapy the future of lung cancer treatment? “The answer is not so obvious, because different mechanisms counteract the immune system and it will be essential to move towards an ever greater personalization of therapies, identifying which mechanisms are involved in the development of tumors of individual patients”.