Immunotherapy: Is it the innovative solution of the future?

What is the immune system made of?

Every day, foreign substances, called “antigens” enter our body. It can be a bacteria, a virus, a parasite, a fungus, a chemical … The role of our immune system is to protect our body against all these substances that can put our health endanger.

The immune system is made up of a set of cells and proteins that work to protect the body from infectious, potentially harmful microorganisms. It also plays a defense role against cancer cells.

It breaks down into two subsystems, the non-specific defense system and the defense system
specific.

Non-specific defense mechanisms

  1. The body’s first line defense begins with the skin. This is an impenetrable barrier for the vast majority of infectious agents, most of which can only enter the body through the mucous membranes such as the mouth, nose, eyes …
  2. The second line of defense involves certain white blood cells, neutrophils and macrophages, which patrol relentlessly throughout the body. If they find intruders there, they
    trigger an alert reaction and flock en masse from the bloodstream to fight and destroy foreign agents by phagocytosis (capture and ingestion).
  3. Some active proteins, mainly secreted by the liver (supplements), attacking bacteria, and interferon, which has antiviral properties, complete the arsenal of immediate defense.
  4. These quickly mobilizable non-specific defenses make up innate immunity.

Specific defense mechanisms

  1. If non-specific defenses are not enough, specific defense mechanisms come into play.
  2. The body first carries out a precise identification of the intruder, which explains the slowness of this defense system: it is only after this recognition step that the production of antibodies specific to each antigen can start.
  3. Antibodies are molecules present in the blood plasma and in the lymph and develop during reactions with antigens. When this reaction has taken place and therefore there has been the production of antibodies, it is said that the individual has acquired immunity.

How does the immune system work?

Our body reacts to an attack with inflammation: the white blood cells go on reconnaissance in order to establish who is the enemy and, thus, allow the body to prepare the most suitable response.

  1. First come the neutrophils and the macrophages, responsible for cleaning up the site. When they are not enough to control the infection, other more specialized white blood cells
    come into play, T lymphocytes
  2. The immune system indeed has a mechanism of “archives”: it keeps in memory all the intruders that it has already fought before.
  3. When a new pathogen arrives, either the antigen is already known and the T lymphocytes specific for this infection are sent to destroy it, or the organism must adapt and produce the antibodies that will be able to overcome it. It takes a while for the new antibodies to be ready: fatigue, inflammation and fever are signals that
    the organization is fighting an intruder.
  4. It is the T4 lymphocytes which give the order for the production of these new antibodies: by means of chemical molecules, the interleukins (cytokines), they stimulate the B lymphocytes, the T8 and NK lymphocytes (Natural Killers).
  5. B lymphocytes will secrete large quantities of antibodies responsible for destroying the secretions of infected cells.
  6. T8 lymphocytes and T lymphocytes, “NK, Natural Killers”, are responsible for destroying infected cells.

What are the different stages of the immune response?

  1. DETECTION OF AN ANTIGEN: the organism is attacked by a foreign element
  2. ARRIVAL OF NEUTROPHILES AND MACROPHAGES (categories of white blood cells)
  3. IF DESTRUCTION OF ALL ANTIGENS (by phagocytosis), immediate recovery without even having the feeling of having been infected. OTHERWISE: “overwhelmed” neutrophils and macrophages
    warn T cells
  4. IF AN AGENT ALREADY KNOWN, specific T cells destroy it. IF AGENT UNKNOWN, T4 lymphocytes enter the scene and stimulate B lymphocytes and T8 and NK (Natural Killers) lymphocytes
  5. B LYMPHOCYTES disarm the attackers
  6. T8 and NK LYMPHOCYTES destroy infected cells.

How does the immune system change over time?

The specific immune system is not acquired from birth: it develops and completes throughout life. After each immune reaction, memory cells are created and ensure a rapid reaction upon further contact with an already known intruder. This explains why the immune system is stronger after each infection.

The immune system of adults is therefore much more developed than that of children, which does not yet have an “archive”.

It experiences optimal functioning during the “adult” period before weakening again. Older people are more susceptible to infections and the complications they cause. They also heal more slowly. It is for this reason that the elderly are recommended to get the flu vaccine.

What is immunotherapy?

Immunotherapy is a treatment that involves the administration of substances that stimulate or modify the immune system.

The immune system can go wrong. He can react:

  1. Either too strongly by rejecting a tissue or organ transplant or by causing hypersensitivity to certain antigens (allergies),
  2. Either too weakly, by deploying too limited defenses against a microbe in the event of an infectious disease,
  3. Or inappropriately in certain autoimmune diseases, the body then making antibodies against its own cells (example: multiple sclerosis).

The goal of immunotherapy is to stimulate the immune mechanisms, that is to say the immune responses when these are insufficient, this is called immunostimulation.

In some cases, immunotherapy makes it possible to curb immunity, this is called immunosuppression, when the immune response is excessive or even undesirable.

Immunotherapy really started in the 1960s, with bone marrow transplants, which transfer immune cells (lymphocytes) from the donor to the recipient.

The available therapies have increased in the last quarter of the 20th century, with the isolation of substances produced during an immune reaction (cytokines) and with the possibility of modifying lymphocytes outside the organism.

Immunotherapy today covers a large family of preventive or curative therapeutic solutions calling on the immune system of individuals.

What are the different immunotherapy strategies?

There is a distinction between passive immunotherapy and active immunotherapy.
Passive immunotherapy : The oldest, has already sought to provide the patient with antibodies against cancer cells along the lines of the serotherapy used for infectious diseases.

  • The use of specific monoclonal antibodies, obtained by genetic engineering from a single cell line called the clone, now makes it possible to effectively replace the injection of serum which was obtained after immunization with a horse or rabbit against human T cells. Monoclonal antibodies are directed against certain T cells that have been activated or against cytokines. The monoclonal antibody technique which makes it possible to produce large quantities of antibodies directed against a specific cell or substance has made it possible to develop effective drugs: trastuzumab
    for certain breast cancers, rituximab in lymphomas, cetuximab for colon cancers, ipilumab against metastatic melanoma.
  • In the absence of obtaining specific antibodies against cancer cells, today we rather use immune mediators, less specific but which prove to be effective, such as interferons.

Active immunotherapy is about stimulating an individual’s own defenses to help them fight a disease.

  • Vaccination is the best known specific active immunostimulation method. This preventive method stimulates the production of memory lymphocytes allowing an effective response at the time of the assault by the identified agent.
  • Equally active but less specific, is the desensitization of allergic patients: the treatment consists in injecting a patient with very small amounts of allergens (substances likely to cause an allergy) in order to arouse in him an awareness of the origin of the manufacture of neutralizing antibodies.

What are the tools of immunotherapy?

The immunotherapy tools can be classified into four main families:

  1. antibodies or antibody fragments,
  2. cellular immunotherapy products,
  3. vaccines, whether therapeutic or preventive,
  4. immunomodulators,

Categories to which are added biomarkers to assess the impact of immunotherapy treatments.

The term “antibody” covers a complex family of whole antibodies or modified or unmodified antibody fragments.
Cellular immunotherapy covers all biological products derived from the preparation of living human cells (notably stem cells). Immunomodulators group together

  • all proteins, DNA, RNA and molecules (with the exception of antibodies) of human, bacterial or fungal origin capable of modulating the immune response – molecules originating from chemical synthesis which can also modulate the immune response
  • proteins inducing tolerance of the body to allergens

What is the benefit of monoclonal antibodies?

The first monoclonal antibody (mAb) was successfully used in 1986 in kidney transplants, then, an anti-TNF, in the treatment of rheumatoid arthritis. Since then, it is especially cancerology that benefits from their development. 41 therapeutic monoclonal antibodies are on the market today. MAbs can be directed against specific antigens of certain cells, against sugars, growth factor receptors. Better understanding their mechanisms of action should make it possible to increase their efficiency.

The use of monoclonal antibodies aims to prevent cell proliferation by blocking the activity of certain receptors encoded by oncogenes. Monoclonal antibodies are used in the treatment of certain cancers, in particular: rituximab indicated for the treatment of patients with stage III-IV follicular lymphoma in the event of chemoresistance or from the second relapse after chemotherapy.

Trastuzumab is administered women with breast cancer resistant to the usual treatment due to the overabundance of a specific receptor in their cells, called HER-2. The presence of this excess receptor leads to the excess production of a protein which, in turn, induces an uncontrolled multiplication of cells.

What is the value of therapeutic vaccines?

Therapeutic vaccination aims to stimulate the immune responses of patients when the disease is already declared. These vaccines, most of which have been developed against cancer, could therefore be used in the future as a curative treatment complementary to surgery, radiotherapy, chemotherapy and hormone therapy. Using the memory capacities of the immune system, they have the advantage of preventing relapses.

Immunotherapy for cancer has long been considered an attractive but ineffective therapeutic approach. Two new approaches to vaccine immunotherapy in patients with prostate cancer or melanoma have been shown to be effective in phase III clinical trials.

In what context are cellular immunotherapies used?

Cell therapy is distinguished from drugs and biomedicines by the use of “tailor-made” cellular products for a given patient.

The objective is to modify, select or proliferate cells from the patient himself or from a donor, in order to treat diseases for which there is no treatment at all or whose treatments are not satisfactory. Several cellular immunotherapy or gene therapy protocols have already been carried out. Thus, the first gene therapy trial to treat patients with severe immune deficiency took place at Necker Hospital in 1999.

Four other gene therapy protocols and four cell therapy protocols have been carried out or initiated since. In addition, two cell therapy trials and two gene therapy trials are in the pre-clinical development phase.

What about immunomodulators?

 Immunomodulatory treatments are frequently used in neurology for conditions affecting the central or peripheral nervous system, such as multiple sclerosis. Immunosuppressive treatments are applied in organ transplants and as a background treatment in a range of autoimmune diseases and chronic inflammatory diseases. Allergen immunotherapy treats allergic respiratory diseases by preventing the appearance of new sensitizations or its worsening in asthma.

Its action is to reduce the sensitivity of the body to the allergen: by gradually modulating the immune response to this allergen, allergen immunotherapy prevents the occurrence of the allergic reaction. Allergen immunotherapy has taken off in recent years, moving from the subcutaneous to the sublingual route. New treatments have recently acquired full-fledged drug status with marketing authorization.

What are the pathologies that immunotherapy can treat?

Many therapeutic areas are concerned: cancer, infectious diseases, inflammatory diseases, skin diseases, bone diseases, diseases of the central nervous system, allergies… Immunotherapy will have a significant impact on four major areas: cancers, infectious diseases, autoimmune diseases and transplants.

Immunotherapy therefore appears to be a promising line of research, because it approaches with frequent approaches common and widespread diseases: cancer, chronic diseases (rheumatoid arthritis, Crohn’s disease, diabetes, etc.). It makes it possible to respond to public health needs not covered because it provides innovative solutions, acting in synergy with other approaches.

How are immunotherapy treatments administered?

Vaccines are conventionally administered by the subcutaneous or intramuscular route, but other routes are being studied, notably the mucosal routes. Antibodies or cells are administered by injection. Research on oral administration is also underway.

What are the side effects of immunotherapy?

The side effects are not related to the family of drugs used in immunotherapy but specific to each of the products. Interferon can cause eye problems, dry skin, fever, body aches, character disturbances. Interleukin, on the other hand, often causes digestive or skin disorders. Desensitizations can cause acute allergic reactions.

Is immunotherapy effective?

Drugs based on beta interferon effectively slow the progression of multiple sclerosis. Ipilumab significantly prolongs the life of patients with metastatic melanoma. Immunotherapy against insect venom is the most effective type of immunotherapy to date with an efficacy rate of around 98%. About 80-85% of people receiving immunotherapy for pollen will notice an improvement in their condition. Immunotherapy also has a certain effectiveness recognized for the treatment of allergies to dust mites, molds, animals.

However, this type of treatment does not guarantee the complete resolution of allergic manifestations, but can have positive impacts on the quality of life in most patients receiving this type of treatment.

What are the scientific and medical issues related to immunotherapy?

The idea of using the immune system mobilized many researchers in the 1990s. But difficult and unsuccessful developments had led to widespread discouragement.

Developments in recent years have generated the momentum that researchers need to develop more potent treatments and combine them with both traditional medicines and other immunotherapies. 23 cancer immunotherapies are currently in development.