Oncological immunotherapy

On 1 October 2018, the Nobel Prize in the field of Medicine was awarded to two great scholars: James P. Allison and Tasuku Honjo.

Their independently conducted research is a milestone in the fight against cancer because they have identified the various mechanisms by which cells in the immune system are able to attack cancer cells and, more specifically, have shown how to remove the ‘brakes’ that prevent the immune system from making an effective and decisive attack.

The two researchers laid the foundations of immunotherapy, now considered the last frontier in the fight against cancer, a disease that affects about 18 million people a year globally.

What do immunotherapy mean?

Immunotherapy means a treatment that uses the patient’s own immune system, or certain of its components, to fight diseases, such as cancer. In oncology the use of immunotherapy has been in an experimental phase for decades, in association with traditional protocols including chemotherapy and radiotherapy;

• However, the successes that have recently been achieved – such as the recovery from acute lymphoblastic leukemia of a child undergoing therapy gene with manipulation of the cells of his immune system – they light up hopefuls for the future. However, let us take a big step back to understand what we are talking about.
• To overcome neoplastic cells, which have the characteristic of reproducing very quickly at the expense of healthy cells, the immunotherapeutic techniques currently in use can act in two ways:

Directly stimulating the body’s immune system to make it more effective in recognizing and destroying cancer cells, Inoculating in the immune system molecules – such as proteins – that strengthen the defense system making it more “intelligent” in finding and eliminating cancer cells.

Oncological immunotherapy is also called biological therapy or biotherapy. Not all techniques work the same way with different cancers: some are very effective for certain types of cancer, and less for others, also because the way they “work” is different. While some therapies merely enhance the immune system in general, others “arm it” (or better, give instructions to some specific components of the body’s defense system) to “kill” specifically the cancerous cells of a certain type of cancer.

What does the immune system do?

Our immune system is a complex mechanism made up of “special” organs and cells that simultaneously defending our body from all internal and external threats. Immune cells – in particular lymphocytes, which are white blood cells – and the substances they produce, travel inside the body to protect it from the attack of pathogenic germs, but are also able, in part, to prevent its spread of a tumor.

The immune system as a whole recognizes all the substances that are normally found in the body. Any “new” element, which is therefore not present in the immune database, as an unknown causes an immediate “alarm” that leads to attacking it. Typical the case of an external microorganism – ex. viruses, bacteria, fungi – which penetrate the body with the intention of creating infectious foci. Immediately our defenses arise, triggering an inflammatory process that aims to render the “enemy” inhospitable, the area or organ in which it has intruded. Our defense mechanism is not always able to recognize the differences between cancer and healthy cells. This lack of alarm unfortunately also occurs when there is a good immune system at the base. Sometimes the tumor cells are detected, but they cannot be blocked, other times they are able to “trick” the immune system or neutralize it. To overcome these obstacles, researchers working on cancer immunotherapy techniques are studying to find and make more and more sophisticated and effective tools to fight cancer cells available to the immune system.

Immunotherapy techniques

The immunotherapy techniques currently available (and therefore successfully tested on patients) are the following:

1. Monoclonal antibodies (mAbs): these are the same proteins of the human immune system in the artificial version, that is to say products in the laboratory. Their usefulness is that they can be structured to attack specific parts of cancer cells. In fact, an antibody is a protein that attacks and blocks antigens, “enemy” proteins. There are many types of antibodies, which once produced in the event of a threat to the body, move between the organs and tissues until they find the antigen to bind to and destroy it. The currently most used mAbs in cancer immunotherapy are:

• Naked monoclonal antibodies. They are simple antibodies, to which no other substances have been applied, and they are the most used in oncological immunotherapy.
• Conjugated monoclonal antibodies. They are antibodies to which chemotherapeutic compounds or radioactive isotopes have been associated and which are therefore used as “carriers” to allow these substances to reach the tumor cells and carry out their destructive action.

2. Immunological checkpoint inhibitors. These drugs substantially unblock the brakes (checkpoints) of the immune system thus allowing recognition and attack on cancer cells. An important competence of the body’s defense system is in fact to distinguish abnormal cells from healthy ones and therefore to attack only the first ones. To make this necessary distinction, the immune system uses molecules or specific cells – defined checkpoints / checkpoints – that must be activated to give the ok to the attack. The problem with checkpoints is that often cancer cells exploit these immune “brakes” to avoid being attacked. Disabling checkpoints removes this extreme defense against neoplastic cells and allows them to be recognized.
3. CAR-T therapy. It combines immune therapy with gene therapy, a hope especially against some forms of leukemia. A first sample of immune cells is taken from the patient, then their DNA is modified to make them able to recognize cancer cells and attack them and, finally, they are re-implanted in the body by infusion.
4. Anticancer vaccines. Anticancer vaccination has a preventive purpose, and provides the body of a healthy subject with tools to attack pathogens that are able to promote the growth of certain types of cancer. These immunizations work just like the others, only instead of protecting the body from flu, tetanus or exanthematous diseases, they defend it from potentially cancerous infections.
5. Non-specific oncologic immunotherapies. These therapies can be administered alone, to generally stimulate the immune system and improve its anti-cancer response, or as adjuvants to traditional therapies. Some “work” with synthetic cytokines (interleukins and interferons in particular), which are inoculated in the body through subcutaneous, intramuscular or intravenous injections. Cytokines are chemical compounds produced by some cells of the immune system whose job is to control the development and function of other immune components (both cells and blood vessels).

Immune or biological therapies are administered in different ways, including intravenous injections, orally, topically, or with an intravesical injection.

Side effects

The side effects that can be caused by immunotherapy are due to the hyperactivity of the immune system. Indeed, it may happen that the immune system attacks, not only the sick cells, but also the healthy ones because it is no longer able to recognize them as such. The side effects, however, may vary depending on the type of immunotherapy and depending on the drug being administered. The most common effects can be:

• fatigue;
• Itching and redness;
• Nausea and vomiting;
• Diarrhea;
• colitis;
• Increased transaminases (enzymes present in the body that are often used as an index to detect the presence of liver damage);
• Altered functioning of endocrine glands, especially thyroid and pituitary glands.

Despite the side effects that can occur, the strong point of immunotherapy is that it does not use drugs that directly target cancer cells, but instead uses molecules and cells from the immune system that are naturally part of the body.