Biological Therapies for Cancer
  1. 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 use vaccines or bacteria to stimulate the body’s immune system to act against cancer cells. These types of biological therapy, which are sometimes referred to collectively as “immunotherapy” or “biological response modifier therapy,” do not target cancer cells directly. Other biological therapies, such as antibodies or segments of genetic material (RNA or DNA), do target cancer cells directly. Biological therapies that interfere with specificmolecules 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 side 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).
  1. What is the immune system and what role does it have in biological therapy for cancer?
The immune system is a complex network of organs, tissues, and specialized cells. It recognizes and destroys foreign invaders, such as bacteria or viruses, as well as some damaged, diseased, or abnormal cells in the body, including cancer cells. An immune response is triggered when the immune system encounters a substance, called an antigen, it recognizes as “foreign.”
White blood cells are the primary players in immune system responses. Some white blood cells, including macrophages and natural killer cells, patrol the body, seeking out foreign invaders and diseased, damaged, or dead cells. These white blood cells provide a general—or nonspecific—level of immune protection.
Other white blood cells, including cytotoxic T cells and B cells, act against specific targets. Cytotoxic T cells release chemicals that can directly destroy microbes or abnormal cells. B cells make antibodies that latch onto foreign intruders or abnormal cells and tag them for destruction by another component of the immune system. Still other white blood cells, including dendritic cells, play supporting roles to ensure that cytotoxic T cells and B cells do their jobs effectively.
It is generally believed that the immune system’s natural capacity to detect and destroy abnormal cells prevents the development of many cancers. Nevertheless, some cancer cells are able to evade detection by using one or more strategies. For example, cancer cells can undergo genetic changes that lead to the loss of cancer-associated antigens, making them less “visible” to the immune system. They may also use several different mechanisms to suppress immune responses or to avoid being killed by cytotoxic T cells (1).
The goal of immunotherapy for cancer is to overcome these barriers to an effective anticancer immune response. These biological therapies restore or increase the activities of specific immune-system components or counteract immunosuppressive signals produced by cancer cells.
  1. What are monoclonal antibodies, and how are they used in cancer treatment?
Monoclonal antibodies, or MAbs, are laboratory-produced antibodies that bind to specificantigens expressed by cancer cells, such as a protein that is present on the surface of cancer cells but is absent from (or expressed at lower levels by) normal cells.
To create MAbs, researchers inject mice with an antigen from human cancer cells. They then harvest the antibody-producing cells from the mice and individually fuse them with a myeloma cell (cancerous B cell) to produce a fusion cell known as a hybridoma. Each hybridoma then divides to produce identical daughter cells or clones—hence the term “monoclonal”—and antibodies secreted by different clones are tested to identify the antibodies that bind most strongly to the antigen. Large quantities of antibodies can be produced by these immortal hybridoma cells. Because mouse antibodies can themselves elicit an immune response in humans, which would reduce their effectiveness, mouse antibodies are often “humanized” by replacing as much of the mouse portion of the antibody as possible with human portions. This is done through genetic engineering.
Some MAbs stimulate an immune response that destroys cancer cells. Similar to the antibodies produced naturally by B cells, these MAbs “coat” the cancer cell surface, triggering its destruction by the immune system. FDA-approved MAbs of this type include rituximab, which targets the CD20 antigen found on non-Hodgkin lymphoma cells, and alemtuzumab, which targets the CD52 antigen found on B-cell chronic lymphocytic leukemia (CLL) cells. Rituximab may also trigger cell death (apoptosis) directly.
Another group of MAbs stimulates an anticancer immune response by binding to receptors on the surface of immune cells and inhibiting signals that prevent immune cells from attacking the body’s own tissues, including cancer cells. One such MAb, ipilimumab, has been approved by the FDA for treatment of metastatic melanoma, and others are being investigated in clinical studies(2).
Other MAbs interfere with the action of proteins that are necessary for tumor growth. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor’s microenvironment that promotes the development of tumor blood vessels. When bound to bevacizumab, VEGF cannot interact with its cellular receptor, preventing the signaling that leads to the growth of new blood vessels.
Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), andtrastuzumab targets the human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from sending their normal growth-promoting signals. They may also trigger apoptosis and activate the immune system to destroy tumor cells.
Another group of cancer therapeutic MAbs are the immunoconjugates. These MAbs, which are sometimes called immunotoxins or antibody-drug conjugates, consist of an antibody attached to a cell-killing substance, such as a plant or bacterial toxin, a chemotherapy drug, or a radioactivemolecule. The antibody latches onto its specific antigen on the surface of a cancer cell, and the cell-killing substance is taken up by the cell. FDA-approved conjugated MAbs that work this way include 90Y-ibritumomab tiuxetan, which targets the CD20 antigen to deliver radioactive yttrium-90 to B-cell non-Hodgkin lymphoma cells; 131I-tositumomab, which targets the CD20 antigen to deliver radioactive iodine-131 to non-Hodgkin lymphoma cells; and ado-trastuzumab emtansine, which targets the HER-2 molecule to deliver the drug DM1, which inhibits cell proliferation, to HER-2 expressing metastatic breast cancer cells.
  1. What are cytokines, and how are they used in cancer treatment?
Cytokines are signaling proteins that are produced by white blood cells. They help mediate and regulate 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 effectsof 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 anddendritic cells (3). INF-alfa may also inhibit the growth of cancer cells or promote their death (4,5). INF-alfa has been approved for the treatment of melanoma, Kaposi sarcoma, and severalhematologic cancers.
Like INFs, ILs play important roles in the body’s normal immune response and in the immune system’s ability to respond to cancer. Researchers have identified more than a dozen distinct 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 cytotoxic T cells and natural killer cells, leading to an enhanced anticancer immune response (6). IL-2 also facilitates the production of antibodies by B cells to further target cancer cells. Aldesleukin, IL-2 that is made in a laboratory, has been approved for the treatment of metastatic kidney cancer and metastatic melanoma. Researchers are currently investigating whether combining aldesleukin treatment with other types of biological therapies may enhance its anticancer effects.
Hematopoietic growth factors are a special class of naturally occurring cytokines. All blood cells arise from hematopoietic stem cells in the bone marrow. Because chemotherapy drugs target proliferating cells, including normal blood stem cells, chemotherapy depletes these stem cells and the blood cells that they produce. Loss of red blood cells, which transport oxygen and nutrients throughout the body, can cause anemia. A decrease in platelets, which are responsible for blood clotting, often leads to abnormal bleeding. Finally, lower white blood cell counts leave chemotherapy patients vulnerable to infections.
Several growth factors that promote the growth of these various blood cell populations have been approved for clinical use. Erythropoietin stimulates red blood cell formation, and IL-11 increases platelet production. Granulocyte-macrophage colony-stimulating factor (GM-CSF) andgranulocyte colony-stimulating factor (G-CSF) both increase the number of white blood cells, reducing the risk of infections. Treatment with these factors allows patients to continue chemotherapy regimens that might otherwise be stopped temporarily or modified to reduce the drug doses because of low blood cell numbers.
G-CSF and GM-CSF can also enhance the immune system’s specific anticancer responses by increasing the number of cancer-fighting T cells. Thus, GM-CSF and G-CSF are used in combination with other biological therapies to strengthen anticancer immune responses.
  1. What are cancer treatment vaccines?
Cancer treatment vaccines are designed to treat cancers that have already developed rather than to prevent them in the first place. Cancer treatment vaccines contain cancer-associatedantigens to enhance the immune system’s response to a patient’s tumor cells. The cancer-associated antigens can be proteins or another type of molecule found on the surface of or inside cancer cells that can stimulate B cells or killer T cells to attack them.
Some vaccines that are under development target antigens that are found on or in many types of cancer cells. These types of cancer vaccines are being tested in clinical trials in patients with a variety of cancers, including prostate, colorectal, lung, breast, and thyroid cancers. Other cancer vaccines target antigens that are unique to a specific cancer type (7-14). Still other vaccines are designed against an antigen specific to one patient’s tumor and need to be customized for each patient. The one cancer treatment vaccine that has received FDA approval, sipuleucel-T, is this type of vaccine.
Because of the limited toxicity seen with cancer vaccines, they are also being tested in clinical trials in combination with other forms of therapy, such as hormonal therapy, chemotherapy,radiation therapy, and targeted therapies. (For more information see Cancer Vaccines.)
  1. What is bacillus Calmette-Guérin therapy?
Bacillus Calmette-Guérin (BCG) was the first biological therapy to be approved by the FDA. It is a weakened form of a live tuberculosis bacterium that 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. How and why BCG exerts this anticancer effect is not well understood, but the efficacy of the treatment is well documented. Approximately 70 percent of patients with early-stage bladder cancer experience a remissionafter BCG therapy (15).
BCG is also being studied in the treatment of other types of cancer (16-18).
  1. What is oncolytic virus therapy?
Oncolytic virus therapy is an experimental form of biological therapy that involves the direct destruction of cancer cells. Oncolytic viruses infect both cancer and normal cells, but they have little effect on normal cells. In contrast, they readily replicate, or reproduce, inside cancer cells and ultimately cause the cancer cells to die. Some viruses, such as reovirus, Newcastle disease virus, and mumps virus, are naturally oncolytic, whereas others, including measles virus, adenovirus, and vaccinia virus, can be adapted or modified to replicate efficiently only in cancer cells. In addition, oncolytic viruses can be genetically engineered to preferentially infect and replicate in cancer cells that produce a specific cancer-associated antigen, such as EGFR or HER-2 (19).
One of the challenges in using oncolytic viruses is that they may themselves be destroyed by the patient’s immune system before they have a chance to attack the cancer. Researchers have developed several strategies to overcome this challenge, such as administering a combination of immune-suppressing chemotherapy drugs like cyclophosphamide along with the virus or “cloaking” the virus within a protective envelope. But an immune reaction in the patient may actually have benefits: although it may hamper oncolytic virus therapy at the time of viral delivery, it may enhance cancer cell destruction after the virus has infected the tumor cells (20-23).
No oncolytic virus has been approved for use in the United States, although H101, a modified form of adenovirus, was approved in China in 2006 for the treatment of patients with head and neck cancer. Several oncolytic viruses are currently being tested in clinical trials. Researchers are also investigating whether oncolytic viruses can be combined with other types of cancer therapies or can be used to sensitize patients’ tumors to additional therapy.
  1. What is gene therapy?
Still an experimental form of treatment, gene therapy attempts to introduce genetic material (DNAor RNA) into living cells. Gene therapy is being studied in clinical trials for many types of cancer.
In general, genetic material cannot be inserted directly into a person's cells. Instead, it is delivered to the cells using a carrier, or “vector.” The vectors most commonly used in gene therapy are viruses, because they have the unique ability to recognize certain cells and insert genetic material into them. Scientists alter these viruses to make them more safe for humans (e.g., by inactivating genes that enable them to reproduce or cause disease) and/or to improve their ability to recognize and enter the target cell. A variety of liposomes (fatty particles) andnanoparticles are also being used as gene therapy vectors, and scientists are investigating methods of targeting these vectors to specific cell types.
Researchers are studying several methods for treating cancer with gene therapy. Some approaches target cancer cells, to destroy them or prevent their growth. Others target healthy cells to enhance their ability to fight cancer. In some cases, researchers remove cells from the patient, treat the cells with the vector in the laboratory, and return the cells to the patient. In others, the vector is given directly to the patient. Some gene therapy approaches being studied are described below.
o    Replacing an altered tumor suppressor gene that produces a nonfunctional protein (or no protein) with a normal version of the gene. Because tumor suppressor genes (e.g., TP53) play a role in preventing cancer, restoring the normal function of these genes may inhibit cancer growth or promote cancer regression.
o    Introducing genetic material to block the expression of an oncogene whose product promotes tumor growth. Short RNA or DNA molecules with sequences complementary to the gene’s messenger RNA (mRNA) can be packaged into vectors or given to cells directly. These short molecules, called oligonucleotides, can bind to the target mRNA, preventing itstranslation into protein or even causing its degradation.
o    Improving a patient's immune response to cancer. In one approach, gene therapy is used to introduce cytokine-producing genes into cancer cells to stimulate the immune response to the tumor.
o    Inserting genes into cancer cells to make them more sensitive to chemotherapy, radiation therapy, or other treatments
o    Inserting genes into healthy blood-forming stem cells to make them more resistant to theside effects of cancer treatments, such as high doses of anticancer drugs
o    Introducing “suicide genes” into a patient's cancer cells. A suicide gene is a gene whose product is able to activate a “pro-drug” (an inactive form of a toxic drug), causing the toxic drug to be produced only in cancer cells in patients given the pro-drug. Normal cells, which do not express the suicide genes, are not affected by the pro-drug.
o    Inserting genes to prevent cancer cells from developing new blood vessels (angiogenesis)
Proposed gene therapy clinical trials, or protocols, must be approved by at least two review boards at the researchers’ institution before they can be conducted. Gene therapy protocols must also be approved by the FDA, which regulates all gene therapy products. In addition, gene therapy trials that are funded by the National Institutes of Health must be registered with the NIH Recombinant DNA Advisory Committee.
  1. What is adoptive T-cell transfer therapy?
Adoptive cell transfer is an experimental anticancer therapy that attempts to enhance the natural cancer-fighting ability of a patient’s T cells. In one form of this therapy, researchers first harvest cytotoxic T cells that have invaded a patient’s tumor. They then identify the cells with the greatest antitumor activity and grow large populations of those cells in a laboratory. The patients are then treated to deplete their immune cells, and the laboratory-grown T cells are infused into the patients.
In another, more recently developed form of this therapy, which is also a kind of gene therapy, researchers isolate T cells from a small sample of the patient’s blood. They genetically modify the cells by inserting the gene for a receptor that recognizes an antigen specific to the patient’s cancer cells and grow large numbers of these modified cells in culture. The genetically modified cells are then infused into patients whose immune cells have been depleted. The receptor expressed by the modified T cells allows these cells to attach to antigens on the surface of the tumor cells, which activates the T cells to attack and kill the tumor cells.
Adoptive T-cell transfer was first studied for the treatment of metastatic melanoma because melanomas often cause a substantial immune response, with many tumor-invading cytotoxic T cells. Adoptive cell transfer with genetically modified T cells is also being investigated as a treatment for other solid tumors, as well as for hematologic cancers (24-29).
  1. What are the side effects of biological therapies?
The side effects associated with various biological therapies can differ by treatment type. However, pain, swelling, soreness, redness, itchiness, and rash at the site of infusion or injectionare fairly common with these treatments.
Less common but more serious side effects tend to be more specific to one or a few types of biological therapy. For example, therapies intended to prompt an immune response against cancer can 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. Biological therapies that provoke an immune system response also pose a risk of severe or even fatal hypersensitivity (allergic) reactions.
Potential serious side effects of specific biological therapies are as follows:
MAbs
o    Flu-like symptoms
o    Severe allergic reaction
o    Lowered blood counts
o    Changes in blood chemistry
o    Organ damage (usually to heart, lungs, kidneys, liver or brain)
Cytokines (interferons, interleukins, hematopoietic growth factors)
o    Flu-like symptoms
o    Severe allergic reaction
o    Lowered blood counts
o    Changes in blood chemistry
o    Organ damage (usually to heart, lungs, kidneys, liver or brain)
Treatment vaccines
o    Flu-like symptoms
o    Severe allergic reaction
BCG
o    Flu-like symptoms
o    Severe allergic reaction
o    Urinary side effects
o    Pain or burning sensation during urination
o    Increased urgency or frequency of urination
o    Blood in the urine
Oncolytic viruses
o    Flu-like symptoms
o    Tumor lysis syndrome: severe, sometimes life-threatening alterations in blood chemistry following the release of materials formerly contained within cancer cells into the bloodstream
Gene therapy
o    Flu-like symptoms
o    Secondary cancer: techniques that insert DNA into a host cell chromosome can cause cancer to develop if the insertion inhibits expression of a tumor suppressor gene or activates an oncogene; researchers are working to minimize this possibility
o    Mistaken introduction of a gene into healthy cells, including reproductive cells
o    Overexpression of the introduced gene may harm healthy tissues
o    Virus vector transmission to other individuals or into the environment
  1. How can people obtain information about clinical trials of biological therapies for cancer?
Both FDA-approved and experimental biological therapies for specific types of cancer are being studied in clinical trials. The names of the biological therapy types listed below are links to descriptions of ongoing clinical trials that are testing those types of biological therapies in cancer patients. These trial descriptions can also 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-funded clinical trials as well as studies conducted by investigators at hospitals and medical centers throughout the United States and around the world.
Monoclonal antibodies
Cytokine therapy
Vaccine therapy
Adoptive T-cell therapy
Oncolytic virus therapy
Gene therapy
DNA oligonucleotide therapy
RNA oligonucleotide therapy
Lasers in Cancer Treatment
1.    What is laser light?
The term “laser” stands for light amplification by stimulated emission of radiation. Ordinary light, such as that from a light bulb, has many wavelengths and spreads in all directions. Laser light, on the other hand, has a specific wavelength. It is focused in a narrow beam and creates a very high-intensity light. This powerful beam of light may be used to cut through steel or to shape diamonds. Because lasers can focus very accurately on tiny areas, they can also be used for very precise surgical work or for cutting through tissue (in place of a scalpel).
2.    What is laser therapy, and how is it used in cancer treatment?
Laser therapy uses high-intensity light to treat cancer and other illnesses. Lasers can be used to shrink or destroy tumors or precancerous growths. Lasers are most commonly used to treat superficial cancers (cancers on the surface of the body or the lining of internal organs) such asbasal cell skin cancer and the very early stages of some cancers, such as cervical, penile,vaginal, vulvar, and non-small cell lung cancer.
Lasers also may be used to relieve certain symptoms of cancer, such as bleeding or obstruction. For example, lasers can be used to shrink or destroy a tumor that is blocking a patient’s trachea(windpipe) or esophagus. Lasers also can be used to remove colon polyps or tumors that are blocking the colon or stomach.
Laser therapy can be used alone, but most often it is combined with other treatments, such assurgery, chemotherapy, or radiation therapy. In addition, lasers can seal nerve endings to reduce pain after surgery and seal lymph vessels to reduce swelling and limit the spread of tumor cells.
3.    How is laser therapy given to the patient?
Laser therapy is often given through a flexible endoscope (a thin, lighted tube used to look at tissues inside the body). The endoscope is fitted with optical fibers (thin fibers that transmit light). It is inserted through an opening in the body, such as the mouth, nose, anus, or vagina. Laser light is then precisely aimed to cut or destroy a tumor.
Laser-induced interstitial thermotherapy (LITT), or interstitial laser photocoagulation, also uses lasers to treat some cancers. LITT is similar to a cancer treatment called hyperthermia, which uses heat to shrink tumors by damaging or killing cancer cells. (More information about hyperthermia is available in the NCI fact sheet Hyperthermia in Cancer Treatment.) During LITT, an optical fiber is inserted into a tumor. Laser light at the tip of the fiber raises the temperature of the tumor cells and damages or destroys them. LITT is sometimes used to shrink tumors in theliver.
Photodynamic therapy (PDT) is another type of cancer treatment that uses lasers. In PDT, a certain drug, called a photosensitizer or photosensitizing agent, is injected into a patient and absorbed by cells all over the patient’s body. After a couple of days, the agent is found mostly in cancer cells. Laser light is then used to activate the agent and destroy cancer cells. Because the photosensitizer makes the skin and eyes sensitive to light afterwards, patients are advised to avoid direct sunlight and bright indoor light during that time. (More information about PDT is available in the NCI fact sheet Photodynamic Therapy for Cancer.)
4.    What types of lasers are used in cancer treatment?
Three types of lasers are used to treat cancer: carbon dioxide (CO2) lasers, argon lasers, and neodymium:yttrium-aluminum-garnet (Nd:YAG) lasers. Each of these can shrink or destroy tumors and can be used with endoscopes.
CO2 and argon lasers can cut the skin’s surface without going into deeper layers. Thus, they can be used to remove superficial cancers, such as skin cancer. In contrast, the Nd:YAG laser is more commonly applied through an endoscope to treat internal organs, such as the uterus, esophagus, and colon.
Nd:YAG laser light can also travel through optical fibers into specific areas of the body during LITT. Argon lasers are often used to activate the drugs used in PDT.
5.    What are the advantages of laser therapy?
Lasers are more precise than standard surgical tools (scalpels), so they do less damage to normal tissues. As a result, patients usually have less pain, bleeding, swelling, and scarring. With laser therapy, operations are usually shorter. In fact, laser therapy can often be done on anoutpatient basis. It takes less time for patients to heal after laser surgery, and they are less likely to get infections. Patients should consult with their health care provider about whether laser therapy is appropriate for them.
6.    What are the disadvantages of laser therapy?
Laser therapy also has several limitations. Surgeons must have specialized training before they can do laser therapy, and strict safety precautions must be followed. Laser therapy is expensive and requires bulky equipment. In addition, the effects of laser therapy may not last long, so doctors may have to repeat the treatment for a patient to get the full benefit.
7.    What does the future hold for laser therapy?

In clinical trials (research studies), doctors are using lasers to treat cancers of the brain andprostate, among others. To learn more about clinical trials, call NCI’s Cancer Information Service at 1–800–4–CANCER or visit the clinical trials page of NCI’s Web site.
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