Immunotherapy Applications

On the occasion of the Day of Immunology (DOI), which is celebrated on April 29th worldwide, we talked to Dr. Carbone Campoverde to learn more about the importance of this specialty and its pathologies and treatments, as it is a day set aside to disseminate it among the public. This year the focus is on IMMUNOTHERAPY.

Immune system

The immune system is composed of a complex system of cells, cell receptors, intracellular proteins and soluble factors that are potential targets for immunotherapy. But if the targets are varied, so are the possible forms of action that can include reconstitution, stimulation, inhibition, blocking, regulation, induction of apoptosis, reprogramming of elements or mechanisms of the immune system. Therefore, the field of application of Immunotherapy is very broad; it ranges from lifelong preventive vaccines, to new therapeutic vaccines against viral and bacterial infections, to the most recent cancer immunotherapy protocols directed against check-points of the immune system.

Immunotherapy Applications

Primary immunodeficiencies

In primary immunodeficiencies, defense reconstitution treatments are used that include intravenous and subcutaneous immunoglobulins, some cytokines and other proteins. In immunodeficiencies whose genetic defect is known, gene therapy protocols are being evaluated that can lead to the cure of several diseases that until now could only be solved with a bone marrow transplant.

Autoimmune diseases

There has been a breakthrough in immunotherapy of inflammation and systemic autoimmune diseases. Anti-TNF antibodies are used in rheumatoid arthritis or inflammatory bowel diseases; anti-IL1 antibodies in different autoinflammatory syndromes; anti-CD20 antibodies to treat selected cases of lupus, vasculitis or pemphigus; anti-IL6 antibodies in different autoimmune diseases, among other examples that have led many patients to achieve remission of their diseases. In addition, biomarkers are emerging that allow us to introduce these biological therapies and some genetic markers (e.g. polymorphisms) that could be useful to detect the best candidates to respond to them. In addition, there is a growing development in the field of cellular tolerogenic therapy in autoimmune diseases with an important impact on the population, such as multiple sclerosis.

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Undoubtedly, the transplant world has benefited from an increasing number of immunotherapy agents used to prevent and treat graft rejection, but also to control infections. Monoclonal antibodies are used for the induction phase of immunosuppression, to treat acute and chronic rejection or to desensitize patients who have anti-HLA antibodies that may jeopardize the graft. Intravenous immunoglobulins also have a role in the management of rejection.

Much progress has been made in the evaluation of tolerogenic cell therapy. American and European multicenter projects are evaluating new forms of immunotherapy based on dendritic cells, regulatory T cells or regulatory B cells to achieve the dream of immunologic tolerance, a situation in which the transplanted patient can maintain a functioning graft without the use of immunosuppressants.

In the field of prevention and treatment of infections in transplantation, the role of intravenous and subcutaneous immunoglobulins in cases of hypogammaglobulinemia after solid organ transplantation or hyperimmune immunoglobulins for the control of specific processes such as cytomegalovirus or hepatitis B virus is being evaluated. Adoptive T-cell based immunotherapy has also been evaluated for the control of viral infections where cytomegalovirus is again an important target.

Cancer immunotherapy

In the area of cancer immunotherapy, one of the most recent advances as a therapeutic strategy is the inhibition of immune check-points to enhance anti-tumor immune activity in some types of cancer.

The immune system has complex control mechanisms (immune checkpoints) used to avoid exaggerated responses that can cause us harm, such as when the system recognizes its own cells as foreign (autoimmunity). Tumor cells can use these immune checkpoint mechanisms to evade the immune system, which until recently has been a barrier to the use of immunotherapy in oncology. Monoclonal antibodies are now available against some proteins expressed by T lymphocytes that have this control function. These include CTLA-4 or PD1, PDL1 proteins, as examples.

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New immunotherapy agents include antibodies, peptides, proteins, cytokines or cells that can facilitate, enhance or even reprogram the action of the innate and/or adaptive immune system against the tumor. One of the challenges will be to achieve an adequate modulation of the immunological mechanisms, which ultimately demonstrates therapeutic benefit with the lowest possible risk.

Allergic diseases

Other applications of immunotherapy are in the field of allergic diseases. In addition to increasingly well-designed allergy vaccines, monoclonal antibodies have emerged that are useful for controlling complex cases of asthma, such as anti-IgE monoclonal antibodies.

Infectious diseases

Immunotherapy has also reached the field of infectious diseases. Hyperimmune gamma globulins are being evaluated for the treatment of influenza A, and the possible role of similar products for the treatment of Ebola patients has been suggested. The field will surely be explored in emerging infections such as that associated with the Zika virus. Monoclonal antibodies have already been produced for the treatment of influenza A or clostridium difficile infection. Monoclonal antibodies against toxins A and B of the latter have been used in association with antibiotics, reducing the recurrence rate of this important cause of hospital morbidity and mortality. Preventive and therapeutic vaccines have been tested to try to control one of the major problems of recent decades, the AIDS virus.

For the control of infections as frequent as those caused by bacteria, the concept of bacterial vaccines is being rescued, as the preparation of killed bacteria, vehicles and routes of administration are being perfected. The enormous potential of mucous membranes as delivery sites for these vaccines is being rediscovered. They potentially stimulate the innate and adaptive immunity system for better control of infections.

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But immunotherapy has also been introduced in other less explored fields such as, for example, in human reproduction. It is very frustrating when a couple is faced with the problem of recurrent miscarriage. This problem can be related to immunological alterations. One of the most studied in recent years are the natural killer cells, for their potential role in the pathogenesis of recurrent miscarriage. The potential role of intravenous immunoglobulins and granulocyte colony-stimulating factors, among others, has been evaluated as a therapeutic strategy to increase the chances that these couples will be able to have the children they so desire.

Immunoglobulins have also been evaluated in women with obstetric antiphospholipid syndrome, in cases in which a new miscarriage occurs despite the use of conventional therapy consisting of heparin and low-dose ASA.

Of course there are many other examples in which immunotherapy has been used, such as in lymphoproliferative syndromes, multiple myeloma, cryoglobulinemia, recurrent uveitis, suppurative hidradenitis, among others.

We also recall that immunosuppressive drugs are part of the therapeutic arsenal of immunotherapy. The advances in pharmacogenomics recently proposed for the selection of candidates for immunosuppression are interesting.

Adequate immunological monitoring of the target components of immunotherapy and of the possible consequences of immunotherapy in relation to patient safety is also a focus of attention on which many teams are focusing their research efforts. It is opportune in this regard to remember that these therapies can produce advers
e events in some patients. One of the objectives of all those involved in their use is the identification of patients at risk of having these events. We have validated biomarkers for different components of the system that may be affected by these therapies.