Biological therapies for cancer application research

Biological therapy uses living organisms, substances from living organisms or synthetic versions of such substances to treat cancer.

Some types of biological therapy use the natural ability of the immune system to detect and destroy cancer cells, while other types directly target cancer cells.

Biological therapies include monoclonal antibodies, cytokines, therapeutic vaccines, Bacillus Calmette-Guerin bacteria, viruses that kill cancer cells, gene therapy, and adopted T lymphocyte transmission.

Side effects of biological therapies can vary depending on the type of treatment, but reactions at the site of application are quite common with these treatments.

What is biological therapy?

Biological therapy involves the use of living organisms, substances derived from living organisms or laboratory-produced versions of such substances for the treatment of disease. Some biological cancer therapies stimulate the body’s immune system to act against cancer cells. These types of biological therapies, sometimes collectively referred to as “immunotherapy,” do not directly attack cancer cells. Other biological therapies, such as antibodies, attack directly cancer cells . Biological therapies that interfere with certain molecules involved in tumor growth and evolution are also called targeted therapies.

For cancer patients, biologic therapies can be used to treat the cancer itself or the side effects of other cancer treatments. Although many forms of biological therapy have already been approved by the Food and Drug Administration (FDA), others are still experimental and available to cancer patients primarily through participation in clinical trials (research studies involving humans).

What is the immune system?

Immune system is a complex network of cells, tissues, organs and matter that they produce. It helps the body fight infections and other diseases.

White blood cells or leukocytes are primarily involved in the responses of the immune system. These cells perform many tasks necessary to protect the body from microbes and abnormal cells that cause disease.

Some types of leukocytes roam the circulatory system in search of foreign invaders and diseased, damaged or dead cells. These white blood cells provide a general – or non-specific – type of immune protection.

Other types of white blood cells, known as lymphocytes, provide targeted protection against certain threats, either from a specific microbe or from a diseased or abnormal cell. The most important groups of lymphocytes responsible for these specific immune responses are B lymphocytes and T lymphocytes.

B cells produce antibodies, which are large secreted proteins that bind to foreign intruders or abnormal cells and help destroy them.

Other types of lymphocytes and leukocytes have supporting functions to ensure that B cells and cytotoxic T cells do their job efficiently. These support cells include helper T lymphocytes and dendritic cells, which help activate both B lymphocytes and cytotoxic T lymphocytes and facilitate their response to specific microbial threats or diseased or abnormal cells.

Antigens are substances in the body that accompany their own cells and microbes that can be recognized by the immune system as harmful to our body. Normal cells in the body have antigens that identify them as “themselves”. Self antigens tell the immune system that normal cells do not pose a threat and should be ignored. In contrast, the immune system recognizes microbes as a possible threat that must be destroyed because they carry foreign antigens or they are not theirs. Cancer cells also often contain antigens, called tumor antigens, that are not present (or are present in lower concentrations) in normal cells.

Can the immune system attack cancer?

The natural ability of the immune system to detect and destroy abnormal cells probably prevents or suppresses the formation of many cancers. Immune cells can sometimes be found in or near tumors. These cells, called lymphocytes that infiltrate the tumor or TIL, are an indication that the immune system is responding to mutated cells. The presence of TIL in a patient’s tumor is often associated with a better patient treatment outcome.

However, cancer cells have a number of ways to avoid detection and destruction by the immune system. For example, cancer cells can:

They undergo genetic changes that reduce the expression of tumor antigens on their surface, making them less “visible” to the immune system.

They have proteins on their surface that inactivate immune cells.

They induce normal cells around the tumor (i.e. in the microenvironment of the tumor) to release substances that suppress the immune response and that promote cell proliferation and tumor survival.

Immunotherapy uses several methods to strengthen the immune system and / or help to overcome cancer defense against the immune system. The goal is to improve the ability of the immune system to detect and destroy cancer.

What types of biological therapies are used to treat cancer?

Several types of biological therapies, especially immunotherapy, are used or formulated to treat cancer. These therapies fight cancer in different ways.

Immune checkpoint inhibitors

How do they work? This type of immunotherapy releases the “brake” of the immune system, which usually prevents excessively strong immune reactions that could damage normal cells as well as abnormal cells. This brake involves proteins on the surface of T lymphocytes called immune checkpoint proteins. When immune checkpoint proteins recognize specific accompanying proteins in other cells, a shutdown signal is sent telling T lymphocytes not to trigger an immune response against those cells.

Two proteins that have been studied very extensively are PD-1 and CTLA-4. Some tumor cells express high concentrations of the accompanying PD-1 protein PD-L1, which causes T lymphocytes to “shut down” and help cancer cells avoid immune destruction. Also, interactions between B7 protein on cell antigen and CTLA-4 are expressed in T cells to prevent other T cells from destroying cells, including cancer cells.

Drugs called immune checkpoints (or modulators of immune checkpoints) prevent the interaction between immune checkpoint proteins and their accompanying proteins, facilitating a strong immune response. The current targets of checkpoint inhibitors are PD-1, PD-L1, and CTLA-4.

How to use:

immune checkpoint inhibitors are approved for the treatment of various types of cancer, including skin cancer, non – lung cancer, small cell lung cancer, bladder cancer, head and neck cancer, liver cancer, Hodgkin ‘s lymphoma, renal cell carcinoma (kidney cancer type) and gastric cancer. An immune checkpoint inhibitor, pembrolizumab (Keitruda®), is used to treat any solid tumor that has high microsatellite instability or cannot be removed surgically. Another immune checkpoint inhibitor, nivolumab (Opdivo®), is used to treat repair abnormalities and major microsatellite instability and metastatic colon cancer that has progressed after treatment with fluoropyrimidine, oxaliplatin, and irinotecan.

Immune cell therapy (also called adopted cell therapy or adopted immunotherapy)

How does it work? This method allows the patient’s own immune cells to attack tumors. There are two methods of cell therapy used to treat cancer. Both involve collecting the patient’s immune cells, multiplying a large number of these cells in the laboratory, and bringing the cells back into the patient.

Lymphocytes that infiltrate the tumor (or TIL). This method uses T lymphocytes that are naturally found in the patient’s tumor, called tumor infiltrating lymphocytes (TIL). TILs that best recognize a patient’s tumor cells in laboratory tests are selected, and these cells are grown in large numbers in the laboratory. The cells are then activated by treatment with signaling proteins of the immune system called cytokines and injected into the patient’s bloodstream.

The idea behind this method is that TILs have already shown the ability to target tumor cells, but there may not be enough of them in the tumor microenvironment to destroy the tumor or overcome the suppressive immune signals that the tumor emits. The introduction of huge amounts of activated TILs can help overcome these barriers.

T and CAR cell therapy

This method is similar, but the patient’s T cells are genetically modified in the laboratory to express a protein known as a chimeric antigen receptor or CAR, before being grown and injected into the patient. CARs are modified forms of a protein called the T-cell receptor, which is expressed on the surface of T-cells. CARs are designed to allow T cells to adhere to certain proteins on the surface of a patient’s cancer cells, which improves his ability to attack cancer cells.

Before receiving expanded T cells, patients also undergo a procedure called lymphatic depletion, which consists of a round of chemotherapy and, in some cases, whole-body radiation. Lymphatic depletion kills other immune cells that can interfere with the efficiency of incoming T cells.

How to use? The adopted T cell transfer was first studied for the treatment of metastatic melanoma because melanomas often cause a significant immune response, with many TILs. The use of activated TILs has been effective for some patients with melanoma and has given encouraging positive results in other cancers (e.g., cervical squamous cell carcinoma and cholangiocarcinoma).

Two T and CAR lymphocyte therapies were approved. Tisagenlecleucel (Kimriah ™) is approved for the treatment of some adults and children with acute lymphoblastic leukemia who do not respond to other treatments and for the treatment of adults with some types of non-Hodgkin’s B-cell lymphoma who have not responded or relapsed in at least two other treatments. In clinical studies, many cancer patients have completely disappeared, and several of these patients have been without cancer for a long time. Ciloleucel akicabtagene (Iescarta () is approved for patients with certain types of non-Hodgkin B cells who have not responded or have relapsed after at least two other treatments. Both therapies involve modifying the patient’s own immune cells.

Therapeutic antibodies

How do they work? Therapeutic antibodies are laboratory-made antibodies that are designed to kill cancer cells. They are a type of cancer-targeted therapy – drugs specifically designed to interact with a specific molecule (or “molecular target”) necessary for cancer cell growth.

Therapeutic antibodies work in many different ways:

They can interfere with a key signaling process that promotes cancer growth and alerts the immune system to destroy cancer cells to which antibodies bind. An example is trastuzumab (Herceptin), which binds to a protein in cancer cells called HER2.

Adherence to the target protein can directly lead to the transition of cancer cells to apoptosis. Examples of this type of therapeutic antibody are rituximab (Ritukan®) and ofatumumab (Arzerra®), which attack a protein on the surface of B lymphocytes called CD20. Similarly, alemtuzumab (Campath®) binds to a protein on the surface of mature lymphocytes called CD52.

They can be bound to a toxic substance that kills the cancer cells to which the antibody binds. A toxic substance can be a poison, such as a bacterial toxin; small molecule drug; a light-sensitive chemical compound (used in photoimmunotherapy); or a radioactive compound used in radioimmunotherapy). Antibodies of this type are sometimes called antibody-drug conjugates (ADCs). Examples of ADCs used for cancer are ado-trastuzumab emtansine, ado-trastuzumab emtasine (Kadcila®), which is taken and destroyed by cancer cells that express HER2 on their surface, and brentuximab vedotin (Adcetris®), which are absorbed by lymphoma cells that surfaces express CD30 and destroy them.

They can bring activated T lymphocytes closer to cancer cells. For example, the therapeutic antibody blinatumomab (Blincito®) binds both to CD19, a tumor-associated antigen that is overexpressed on the surface of leukemia cells, and to CD3, a glycoprotein on the surface of T cells that is part of the T lymphocyte receptor. Blinatumomab contacts leukemia cells with T lymphocytes, resulting in activation of T lymphocytes and cytotoxic T lymphocytes against CD19-expressing leukemia cells.

Other immunotherapies combine other molecules of the immune system (which are not antibodies) and substances that destroy cancer. For example, denileucine diphthytox (ONTAK®) contains interleukin-2 (IL-2) bound to a toxin produced by the bacterium Corinebacterium diphtheria, which causes diphtheria. Denileukin diphtheria uses its share of IL-2 to attack cancer cells that have IL-2 receptors on their surface, allowing the diphtheria toxin to destroy them.

How are they used? Many therapeutic antibodies are approved for the treatment of a wide range of cancers.

Therapeutic vaccines

How do they work? Cancer vaccines are designed to treat existing cancers by strengthening the body’s natural defenses against cancer. The purpose is to slow or stop the growth of cancer cells; to shrink the tumor; stopping the recurrence of cancer; destruction of cancer cells that are not killed by other forms of treatment.

The purpose of cancer vaccines is to introduce one or more cancer antigens into the body that cause an immune response that eventually destroys the cancer cells.

Vaccines for the treatment of cancer can be made from the patient’s own cells (that is, they are modified in such a way as to create an immune response to characteristics that are unique to the patient’s specific tumor) or from substances (antigens) produced by certain types of tumors. , they generate an immune response in each patient whose tumor produces antigen).

The first FDA-approved cancer vaccine, sipuleucel-T (Provenge®), is tailored for each patient. It is designed to stimulate the immune response to prostate acid phosphatase (PAP), an antigen found in most prostate cancer cells. The vaccine is made by isolating immune cells called dendritic cells, which are a type of antigen-presenting cell (APC), from a patient’s blood. These cells are sent to a vaccine manufacturer, where they are grown together with a protein called PAP-GM-CSF. . This protein consists of PAPs associated with a protein called granulocyte macrophage colony stimulating factor (GM-CSF), which stimulates the immune system and improves antigen presentation.

Cells representing antigens cultured PAP-GM-CSF are the active component of sipuleucel-T. These cells are injected into the patient. Although the exact mechanism of action of sipuleucel-T is not known, APC cells that have occupied PAP-GM-CSF appear to stimulate T lymphocytes of the immune system to kill PAP-expressing tumor cells.

The first FDA-approved oncolytic viral therapy, talimogen laherparepvec (T-VEC or Imligic®), is also considered a type of vaccine. It is based on the herpes simplex virus type 1 and includes a gene that encodes GM-CSF. Although this oncolytic virus can infect both cancer cells and normal cells, normal cells have mechanisms to destroy the virus, while cancer cells do not. T-ECV is injected directly into the tumor. As the virus replicates, it causes the cancer cells to explode and die. Dying cells release new viruses, GM-CSF and various tumor-specific antigens. They can stimulate an immune response against cancer cells throughout the body.

How are they used? Sipuleucel-T is used to treat prostate cancer that has metastasized in men who have few or no symptoms and whose cancer is hormone resistant (does not respond to hormonal treatment). ECV-T is used to treat some patients with metastatic melanoma that cannot be removed surgically.

Substances that modulate the immune system

How do they work? Substances that modulate immunity strengthen the body’s immune response against cancer. These substances include proteins that usually help regulate or modulate the activity of the immune system, microbes and drugs.

Cytokines These signaling proteins are naturally produced by white blood cells. They help mediate and fine-tune immune responses, inflammation and hematopoiesis (formation of new blood cells). There are two types of cytokines used to treat cancer patients: Interferon Interferons (INF) and Interleukins (IL). The third type, called hematopoietic growth factor, is used to control some of the side effects of some chemotherapy regimens.

The researchers found that one type of interferon, interferon-α, can improve a patient’s immune response to cancer cells by activating some white blood cells, such as natural killer cells and dendritic cells. Interferon-α can also inhibit the growth of cancer cells or accelerate their death.

Researchers have identified more than a dozen different interleukins, including interleukin-2, also called T-cell growth factor. Interleukin-2 is naturally produced by activated T cells. It increases the proliferation of white blood cells, including cytotoxic T lymphocytes and natural killer cells, resulting in a better immune response against cancer. Interleukin-2 also facilitates the production of antibodies by B lymphocytes for further attack on cancer cells.

Hematopoietic growth factors are a special class of natural cytokines. They promote the growth of different populations of blood cells that are depleted by chemotherapy. Erythropoietin stimulates the production of red blood cells, and interleukin-11 increases platelet production. Granulocyte macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF) stimulate lymphocyte growth, reducing the risk of infection.

Granulocyte colony stimulating factor and granulocyte-macrophage colony stimulating factor may also enhance specific anticancer responses of the immune system by increasing the number of cancer-fighting T lymphocytes.

Bacillus of Calmette-Guerin (BCG). The weakened form of live TB bacteria does not cause disease in humans. It was first used in medicine as a vaccine against tuberculosis. When inserted directly into the bladder with a catheter, the Calmette-Guerin bacillus stimulates a general immune response that is directed not only at the foreign bacteria themselves but also at the bladder cancer cells. The exact mechanism of this anticancer effect is not well understood, but treatment is effective.

Immunomodulatory drugs (also called biological response modifiers). These drugs are powerful modulators of the body’s immune system. They include thalidomide (Thalomid®); lenalidomide (Revlimid®) and pomalidomide (Pomalist®), thalidomide derivatives having a similar structure and function; and imiquimod (Aldara®, Ziclara®).

It is not entirely clear how thalidomide and its two derivatives stimulate the immune system, but they promote the secretion of IL-2 from cells and inhibit the ability of tumors to form new blood vessels that support their growth (a process called angiogenesis). Imiquimod is a cream that is applied to the skin. It causes cells to release cytokines, especially INF-α, IL-6 and TNF-α (a molecule that participates in inflammation).

How are they used? Most substances that modulate the immune system are used to treat advanced cancer. Some are used as part of a support scheme. For example, recombinant and biologically similar forms of GM-CSF and G-CSF are used in combination with other immunotherapies to boost the immune response against cancer by stimulating white blood cell growth.

What are the side effects of biological therapies?

The side effects of biologic therapies generally reflect immune system stimulation and may vary according to the type of therapy and the way individual patients respond to it.

However, pain, inflammation, irritation, redness of the skin, itching and rash at the site of infusion or injection are quite common with these treatments. They can also cause a variety of flu-like symptoms, including fever, chills, weakness, dizziness, nausea or vomiting, muscle or joint pain, fatigue, headaches, occasional shortness of breath, and high or low blood pressure. Some immunotherapies that trigger an immune system reaction also cause a risk of hypersensitivity reactions (allergies), even fatal ones.

Long-term side effects (especially immune checkpoint inhibitors) include autoimmune syndromes and acute onset diabetes.

Possible serious side effects of immunotherapy are:

Immune checkpoint inhibitors

Reactions that damage organs caused by immune activity and include the digestive system, liver, skin, nervous system, heart and glands that produce hormones. These reactions can cause pneumonitis, colitis, hepatitis, nephritis and renal failure, myocarditis (inflammation of the heart muscle), hypothyroidism and hyperthyroidism.

Immune cell therapy

Cytokine release syndrome (CAR and T cell therapy)

Capillary leak syndrome (TIL therapy)

Therapeutic antibodies and other immune system molecules

Cytokine release syndrome (blinatumomab)

Infusion reactions, capillary leakage syndrome and poor visual acuity (denileucine diphthotox)

Therapeutic vaccines

Flu-like symptoms

Severe allergic reaction

Stroke (sipuleucel-T)

Tumor lysis syndrome, herpes viral infection (T-VEC)

Immune system modulators

Flu-like symptoms, severe allergic reaction, low blood counts, changes in blood chemistry, organ damage (cytokines)

Flu-like symptoms, severe allergic reaction, urinary side effects (BCG)

Serious birth defects if taken during pregnancy, blood clots, venous embolism, neuropathy (thalidomide, lenalidomide, pomalidomide)

Skin reactions (imiquimod)

What are the current research on cancer immunotherapy?

Researchers are focusing on several important fields to improve the effectiveness of cancer immunotherapy, including:

Methods for overcoming resistance to cancer immunotherapy. Researchers are testing combinations of different immune checkpoint inhibitors, as well as immune checkpoint inhibitors in combination with a wide range of other immunotherapies, molecularly targeted cancer therapies and radiation, as ways to overcome therapeutic drug resistance. Tumors on immunotherapy.

Identification of biomarkers that predict response to immunotherapy. Not everyone receiving immunotherapy will respond to treatment. Identification of biomarkers that predict the response is the main field of research.

Identification of new cancer-related antigens – so-called neoantigens – that may be more effective in stimulating immune responses than known antigens.

Non-invasive strategies for isolating immune cells that respond to tumors that express neoantigens.

Understand better the mechanisms by which cancer cells avoid or suppress the immune response against cancer. A better understanding of how cancer cells manipulate the immune system could lead to the formulation of drugs that block these processes.

Proximity to infrared photoimmunotherapy. This method uses infrared light to activate targeted destruction of cancer cells in the body (December 14-14).

Where can I find information on immunotherapy clinical trials?

In clinical trials, they are evaluated and approved by the FDA and experimental immunotherapy for certain types of cancer. Descriptions of ongoing clinical trials examining the types of immunotherapy in cancer patients can be found in the List of Cancer Clinical Trials on the NCI website. The NCL clinical trial list includes all NCI-sponsored clinical trials conducted in the United States and Canada, including at the NIH Clinical Center in Bethesda, Maryland. For information in English on other ways to search the list, see Help Find NCI-Supported Clinical Trials.

Otherwise, call the NCI Contact Center at 1-800-422-6237 (1-800-4-RAK) for information on clinical trials of immunotherapies.

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