Breaking New Ground in Biological Therapies for Cancer

What is biological therapy?

Biological therapy involves the use of living organisms, substances derived from living organisms, or laboratory-produced versions of such substances to treat disease. Some biological therapies for cancer stimulate the body’s immune system to act against cancer cells. These types of biological therapy, which are sometimes referred to collectively as “immunotherapy,” do not target cancer cells directly. Other biological therapies, such as antibodies, do target cancer cells directly. Biological therapies that interfere with specific molecules involved in tumor growth and progression are also referred to as targeted therapies. (For more information, see Targeted Cancer Therapies.)

For patients with cancer, biological therapies may be used to treat the cancer itself or the adverse effects of other cancer treatments. Although many forms of biological therapy have been approved by the U.S. Food and Drug Administration (FDA), others remain experimental and are available to cancer patients principally through participation in clinical trials (research studies involving people).

What is the immune system?

The immune system is a complex network of cells, tissues, organs, and the substances they make. It helps the body fight infections and other diseases.

• White blood cells, or leukocytes, play the main role in immune responses. These cells carry out the many tasks required to protect the body against disease-causing microbes and abnormal cells.
• Some types of leukocytes patrol the circulatory system, seeking foreign invaders, such as microbes and pathogens, and diseased, damaged, or dead cells. These white blood cells provide a general—or nonspecific—type of immune protection.
• Other types of leukocytes, known as lymphocytes, provide targeted protection against specific threats, whether from a specific microbe or a diseased or abnormal cell. The most important groups of lymphocytes responsible for these specific immune responses are B cells and T cells.
  • B cells make antibodies, which are large, secreted proteins that bind to and help destroy foreign invaders or abnormal cells.
  • Killer T cells, which are also known as cytotoxic T cells, kill infected or abnormal cells by releasing toxic chemicals or by prompting the cells to self-destruct (in a process known as apoptosis).
• Other types of lymphocytes and leukocytes play supporting roles to ensure that B cells and killer T cells do their jobs effectively. These supporting cells include helper T cells and dendritic cells, which help activate both B cells and killer T cells and enable them to respond to specific threats from a microbe or a diseased or abnormal cell.

Antigens are substances on the body’s own cells and on microbes that can be recognized by the immune system. Normal cells in the body have antigens that identify them as “self.” Self antigens tell the immune system that normal cells are not a threat and should be ignored. In contrast, microbes are recognized by the immune system as a potential threat that should be destroyed because they carry foreign, or non-self, antigens. Cancer cells also often contain antigens, called tumor antigens, that are not present (or are present at lower levels) on normal cells.

Can the immune system attack cancer?

The natural ability of the immune system to detect and destroy abnormal cells likely prevents or suppresses the development of many cancers. Immune cells are sometimes found in and around tumors. These cells, called tumor-infiltrating lymphocytes or TILs, are an indication that the immune system is responding to the tumor. The presence of TILs in a patient’s tumor is often associated with a better outcome in the patient.

However, cancer cells have various ways to evade detection and destruction by the immune system. For example, cancer cells can:

• Undergo genetic changes that cause them to reduce the expression of tumor antigens on their surface, making them less “visible” to the immune system
• Have proteins on their surface that inactivate immune cells
• Induce normal cells around the tumor (i.e, in the tumor microenvironment) to release substances that suppress immune responses and that promote tumor cell proliferation and survival.

Immunotherapy uses various approaches to strengthen the immune system and/or help it surmount the cancer’s defenses against the immune system. The goal is to improve the ability of the immune system to detect and destroy cancer.

What types of biological therapy are used to treat cancer?

Several types of biological therapies, especially immunotherapies, are being used or developed for cancer treatment. These therapies fight cancer in different ways.

Immune Checkpoint Inhibitors

How they work: This type of immunotherapy releases a “brake” on the immune system that normally prevents overly strong immune responses that might damage normal cells as well as abnormal cells. This brake involves proteins on the surface of T cells called immune checkpoint proteins. When immune checkpoint proteins recognize specific partner proteins on other cells, an “off” signal is sent that tells the T cell not to mount an immune response against those cells.

Two widely studied immune checkpoint proteins are PD-1 and CTLA-4. Some tumor cells express high levels of the PD-1 partner protein PD-L1, which causes T cells to shut down and helps the cancer cells evade immune destruction. Similarly, interactions between B7 proteins on antigen-presenting cells and CTLA-4 that is expressed on T cells prevents T cells from killing other cells, including cancer cells.

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

How they are used: Immune checkpoint inhibitors are approved to treat a variety of cancer types, including skin cancer, non-small cell lung cancer, bladder cancer, head and neck cancer, liver cancer, Hodgkin lymphoma, renal cell cancer and stomach cancer. One immune checkpoint inhibitor, pembrolizumab (Keytruda®), is used to treat any solid tumor that is microsatellite instability-high or mismatch repair deficient and has spread or cannot be removed by surgery. Another immune checkpoint inhibitor, nivolumab (Opdivo®), is used to treat mismatch repair deficient and microsatellite instability-high metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan hydrochloride.

Immune Cell Therapy (also called Adoptive Cell Therapy or Adoptive Immunotherapy)

How it works: This approach makes a patient’s own immune cells better able to attack tumors. There are two general approaches to adoptive cellular therapy for cancer treatment. Both involve collecting a patient’s own immune cells, growing large numbers of these cells in the laboratory, and then infusing the cells back into the patient.

• Tumor-infiltrating lymphocytes (or TILs). This approach uses T cells that are naturally found in a patient’s tumor, called tumor-infiltrating lymphocytes (TILs). TILs that best recognize the patient's tumor cells in laboratory tests are selected, and these cells are grown to large numbers in the laboratory. The cells are then activated by treatment with immune system signaling proteins called cytokines and infused into the patient’s bloodstream.
  
  The idea behind this approach is that the TILs have already shown the ability to target tumor cells, but there may not be enough of them in the tumor microenvironment to kill the tumor or to overcome the immune suppressive signals that the tumor is releasing. Introducing massive amounts of activated TILs can help to overcome these barriers.
• CAR T-cell therapy. This approach 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 they are grown and infused into the patient. CARs are modified forms of a protein called a T-cell receptor, which is expressed on the surface of T cells. The CARs are designed to allow the T cells to attach to specific proteins on the surface of the patient’s cancer cells, improving their ability to attack the cancer cells.

Before receiving the expanded T cells, patients also undergo a procedure called lymphodepletion, which consists of a round of chemotherapy and, in some cases, whole-body radiation. The lymphodepletion gets rid of other immune cells that can impede the effectiveness of the incoming T cells.

How it is used: Adoptive T-cell transfer was first studied for the treatment of metastatic melanoma because melanomas often cause a substantial immune response, with many TILs. The use of activated TILs has been effective for some patients with melanoma and has produced encouraging positive findings in other cancers (e.g., cervical squamous cell carcinoma and cholangiocarcinoma).

Two CAR T-cell therapies have been approved. Tisagenlecleucel (Kymriah™) is approved for treatment of some adults and children with acute lymphoblastic leukemia that is not responding to other treatments and for treatment of adults with certain types of B-cell non-Hodgkin lymphoma who have not responded to or who have relapsed after at least two other kinds of treatment. In clinical trials, many patients’ cancers have disappeared entirely, and several of these patients have remained cancer free for extended periods. Axicabtagene ciloleucel (Yescarta™) is approved for patients with certain types of B-cell non-Hodgkin lymphoma who have not responded to or who have relapsed after at least two other kinds of treatment. Both therapies involve the modification of a patient’s own immune cells.

Therapeutic Antibodies

How they work: Therapeutic antibodies are antibodies made in the laboratory that are designed to destroy cancer cells. They are a type of targeted cancer therapy—drugs that are designed specifically to interact with and block a specific molecule (or “molecular target”) that is necessary for cancer cell growth. More information about targeted therapy is available in NCI’s Targeted Cancer Therapies fact sheet.

Therapeutic antibodies work in many different ways:

• They may both interfere with a key signaling process that promotes the growth of the cancer and alert the immune system to destroy cancer cells to which the antibody is attached. Trastuzumab (Herceptin), which binds to a protein on some cancer cells called HER2, is an example.
• Their binding to the target protein may directly cause cancer cells to undergo apoptosis. Examples of this type of therapeutic antibody are rituximab (Rituxan®) and ofatumumab (Arzerra®), both of which target a protein on the surface of B lymphocytes called CD20. Similarly, alemtuzumab (Campath®), binds a protein on the surface of mature lymphocytes called CD52.
• They may be linked to a toxic substance that kills cancer cells to which the antibody binds. The toxic substance can be a poison, such as a bacterial toxin; a small-molecule drug; a light-sensitive chemical (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 include ado-trastuzumab emtansine (Kadcyla®), which is taken up by and kills cancer cells that express HER2 on their surface, and brentuximab vedotin (Adcetris®), which is taken up by and kills lymphoma cells that express CD30 on their surface.
• They may bring activated T cells into close proximity to cancer cells. For example, the therapeutic antibody blinatumomab (Blincyto®) binds to both CD19, a tumor-associated antigen that is overexpressed on the surface of leukemia cells, and CD3, a glycoprotein on the surface of T cells that is part of the T-cell receptor. Blinatumomab brings leukemia cells into contact with T cells, resulting in T-cell activation and a killer T-cell response against CD19-expressing leukemia cells.

Other immunotherapies combine other (non-antibody) immune system molecules and cancer-killing agents. For example, denileukin diftitox (ONTAK®) consists of the cytokine interleukin-2 (IL-2) attached to a toxin produced by the bacterium Corynebacterium diphtheria, which causes diphtheria. Denileukin diftitox uses its IL-2 portion to target cancer cells that have IL-2 receptors on their surface, allowing the diphtheria toxin to kill them.

How they are used: Many therapeutic antibodies have been approved to treat a wide variety of cancers.

Therapeutic Vaccines

How they work: Cancer treatment vaccines are designed to treat cancers that have already developed by strengthening the body’s natural defenses against the cancer. They are intended to delay or stop cancer cell growth; to cause tumor shrinkage; to prevent cancer from coming back; or to eliminate cancer cells that have not been killed by other forms of treatment.

The idea behind cancer treatment vaccines is that introducing one or more cancer antigens into the body will cause an immune response that ultimately kills the cancer cells.

Cancer treatment vaccines may be made from a patient’s own tumor cells (that is, they are customized so that they mount an immune response against features that are unique to a specific patient’s tumor), or they may be made from substances (antigens) that are produced by certain types of tumors (that is, they mount an immune response in any patient whose tumor produces the antigen).

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

Antigen-presenting cells cultured with PAP-GM-CSF are the active component of sipuleucel-T. These cells are infused into the patient. Although the precise mechanism of action of sipuleucel-T is not known, it appears that the antigen-presenting cells that have taken up PAP-GM-CSF stimulate T cells of the immune system to kill tumor cells that express PAP.

The first FDA-approved oncolytic virus therapy, talimogene laherparepvec (T-VEC, or Imlygic®), is also considered a type of vaccine. It is based on herpes simplex virus type 1 and includes a gene that codes for GM-CSF. Although this oncolytic virus can infect both cancer and normal cells, normal cells have mechanisms to kill the virus whereas cancer cells do not. T-VEC is injected directly into a tumor. As the virus replicates, it causes cancer cells to burst and die. The dying cells release new viruses, GM-CSF, and a variety of tumor-specific antigens that can stimulate an immune response against cancer cells throughout the body.

How they are 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 refractory (does not respond to hormone treatment). T-VEC is used to treat some patients with metastatic melanoma that cannot be removed by surgery.

Immune-Modulating Agents

How they work: Immune-modulating agents enhance the body’s immune response against cancer. These agents include proteins that normally help regulate, or modulate, immune system activity; 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 (new blood cell formation). Two types of cytokines are used to treat patients with cancer: interferons (INFs) and interleukins (ILs). A third type, called hematopoietic growth factors, is used to counteract some of the side effects of certain chemotherapy regimens.
• Researchers have found that one type of INF, INF-alfa, can enhance a patient’s immune response to cancer cells by activating certain white blood cells, such as natural killer cells and dendritic cells (1). INF-alfa may also inhibit the growth of cancer cells or promote their death (2, 3).
  
• Researchers have identified more than a dozen ILs, including IL-2, which is also called T-cell growth factor. IL-2 is naturally produced by activated T cells. It increases the proliferation of white blood cells, including killer T cells and natural killer cells, leading to an enhanced anticancer immune response (4). IL-2 also facilitates the production of antibodies by B cells to further target cancer cells.
  
• Hematopoietic growth factors are a special class of naturally occurring cytokines. They promote the growth of various blood cell populations that are depleted by chemotherapy. Erythropoietin stimulates red blood cell formation, and IL-11 increases platelet production. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) both increase the number of white blood cells, reducing the risk of infections.
  G-CSF and GM-CSF can also enhance the immune system’s specific anticancer responses by increasing the number of cancer-fighting T cells.
• Bacillus Calmette-Guérin (BCG). This weakened form of a live tuberculosis bacterium does not cause disease in humans. It was first used medically as a vaccine against tuberculosis. When inserted directly into the bladder with a catheter, BCG stimulates a general immune response that is directed not only against the foreign bacterium itself but also against bladder cancer cells. The exact mechanism this anticancer effect is not well understood, but the treatment is effective.
• Immunomodulatory drugs (also called biological response modifiers). These drugs are strong modulators of the body’s immune system. They include thalidomide (Thalomid®); lenalidomide (Revlimid®) and pomalidomide (Pomalyst®), derivatives of thalidomide that have a similar structure and function; and imiquimod (Aldara®, Zyclara®).
  
  It is not entirely clear how thalidomide and its two derivatives stimulate the immune system, but they promote the IL-2 secretion from cells and inhibit the ability of tumors to form new blood vessels to support their growth (a process called angiogenesis). Imiquimod is a cream that is applied to the skin. It causes cells to release cytokines, mainly INF-alpha, IL-6, and TNF-alpha (a molecule involved in inflammation).

How they are used: Most immune-modulating agents are used for treatment of advanced cancer. Some are used as part of a supportive care regimen. For example, recombinant and biosimilar forms of GM-CSF and G-CSF are used in combination with other immunotherapies to strengthen anticancer immune responses by stimulating the growth of white blood cells.

What are the side effects of biological therapies?

The side effects of biological therapies mainly reflect the stimulation of the immune system and can differ by the type of therapy and by how individual patients react to it.

Pain, swelling, soreness, redness, itchiness, and rash at the site of infusion or injection are fairly common with these treatments. They can also cause an array of flu-like symptoms, including fever, chills, weakness, dizziness, nausea or vomiting, muscle or joint aches, fatigue, headache, occasional breathing difficulties, and lowered or heightened blood pressure. Some immunotherapies that provoke an immune system response also pose a risk of severe or even fatal hypersensitivity (allergic) reactions.

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

Potentially serious side effects of specific immunotherapies include:

Immune Checkpoint Inhibitors

• Organ-damaging immune-mediated reactions involving the digestive system, liver, skin, nervous system, and heart and in the hormone-producing glands. These reactions can cause immune-mediated pneumonitis, colitis, hepatitis, nephritis and renal (kidney) dysfunction, myocarditis (inflammation of the heart muscle), and hypothyroidism and hyperthyroidism.

Immune Cell Therapy

• Cytokine release syndrome (CAR T-cell therapy)
• Capillary leak syndrome (TIL therapy)

Therapeutic Antibodies and Other Immune System Molecules

• Cytokine release syndrome (blinatumomab)
• Infusion reactions, capillary leak syndrome, and loss of visual acuity (denileukin diftitox)

Therapeutic Vaccines

• Flu-like symptoms
• Severe allergic reaction
• Stroke (Sipuleucel-T)
• Tumor lysis syndrome, herpes virus infection (T-VEC)

Immune System Modulators

• Flu-like symptoms, severe allergic reaction, lowered blood counts, changes in blood chemistry, organ damage (cytokines)
• Flu-like symptoms, severe allergic reaction, urinary side effects (BCG)
• Severe birth defects if taken during pregnancy, blood clots/venous embolism, neuropathy (thalidomide, lenalidomide, pomalidomide)
• Skin reactions (imiquimod)

What is the ongoing research on cancer immunotherapy?

Researchers are focusing on several major areas to improve the effectiveness of cancer immunotherapy, including:

• Approaches to overcome resistance to cancer immunotherapy. Researchers are testing combinations of multiple immune checkpoint inhibitors, as well as immune checkpoint inhibitors in combination with a wide range of other immunotherapies, molecularly targeted cancer therapies, and radiation therapy, as ways to overcome therapeutic resistance of tumors to immunotherapy (5, 6).
• Identification of biomarkers that predict response to immunotherapy. Not everyone who receives immunotherapy will respond to the treatment. Identification of biomarkers that predict response is a major area of research (7, 8).
• Identification of novel cancer-associated antigens—so-called neoantigens—that may be more effective in stimulating immune responses than the already known antigens (9, 10).
• Noninvasive strategies to isolate neoantigen-expressing tumor-reactive immune cells (11).
• Learning more about the mechanisms by which cancer cells evade or suppress anticancer immune responses. A better understanding of how cancer cells manipulate the immune system could lead to the development of drugs that block those processes.
• Near-infrared photoimmunotherapy. This approach uses infrared light to activate the targeted destruction of cancer cells in the body (12–14).

Where can I find information about clinical trials of immunotherapies?

Both FDA-approved and experimental immunotherapies for specific types of cancer are being studied in clinical trials. Descriptions of ongoing clinical trials that are testing types of immunotherapies in cancer patients can be accessed by searching NCI’s list of cancer clinical trials on the NCI website. NCI’s list of cancer clinical trials includes all NCI-supported clinical trials that are taking place across the United States and Canada, including the NIH Clinical Center in Bethesda, MD. For information about other ways to search the list, see Help Finding NCI-Supported Clinical Trials.

Alternatively, call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237) for information about clinical trials of immunotherapies.

References

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