Information presented in this section about the use of Newcastle disease virus (NDV) in the treatment of human cancer is summarized in a table located at the end of the section.

NDV is a paramyxovirus that causes Newcastle disease in a wide variety of birds (most notably, in chickens). Reviewed in [1-4] This often fatal disease is characterized by inflammation of respiratory tract and of either the brain or the gastrointestinal tract. Reviewed in [1-3,5,6] NDV can also infect humans, but, in humans, it is generally not very virulent, causing only mild flu-like symptoms or conjunctivitis and/or laryngitis. Reviewed in [1,3,7-15] The perception that NDV can replicate up to 10,000 times better in human cancer cells than in most normal human cells [13,16-20] Reviewed in [2,7-11,14,21-24] has prompted much interest in this virus as a potential anticancer agent. NDV has been labeled as a complementary and alternative medicine treatment because it is widely believed to be nontoxic; Reviewed in [15] however, this virus has been studied extensively by the conventional medical community.

The genetic material of NDV is RNA rather than DNA. Reviewed in [1,4,14,19,24-28] As with other types of viruses, essentially all of NDV’s replication cycle takes place inside infected cells, which are also known as host cells. Reviewed in [14,19,27,29] During a replication cycle, new virus proteins and copies of the NDV genetic material (i.e., genome) are made in the host cell’s cytoplasm. NDV is also an enveloped virus, which means that progeny virus particles are released from infected cells by budding off from them. Reviewed in [19,27,30] In this process, single copies of the NDV genome become wrapped in an outer coat (i.e., an envelope) that is made from a small piece of the host cell’s plasma membrane. Generally, the NDV outer coat contains only virus proteins that have been specifically inserted into the host cell's plasma membrane; Reviewed in [19,25,29,30] however, some host cell proteins may be included as well. Reviewed in [31,32] Two specific virus proteins, hemagglutinin-neuraminidase and the fusion protein, are the main NDV proteins found in the outer coat of isolated virus particles. Reviewed in [4,19,25,27]

There are many different strains of NDV, and they have been classified as either lytic or nonlytic for human cells. Lytic strains and nonlytic strains both appear to replicate much more efficiently in human cancer cells than they do in most normal human cells,[13,16-21] Reviewed in [14,33] and viruses of both strain types have been investigated as potential anticancer agents. One major difference between lytic strains and nonlytic strains is that lytic strains are able to make infectious progeny virus particles in human cells, whereas nonlytic strains are not. Reviewed in [14,19,25-27,34] This difference is due to the ability of lytic strains to produce activated hemagglutinin-neuraminidase and fusion protein molecules in the outer coat of progeny viruses in human cells. The progeny virus particles made by nonlytic strains contain inactive versions of these molecules. Activated hemagglutinin-neuraminidase and fusion protein molecules are required for NDV to enter a cell to replicate. Initial binding of NDV to a host cell takes place through the interaction of hemagglutinin-neuraminidase molecules in the virus coat with sialic-acid –containing molecules (i.e., gangliosides) on the surface of the cell. It is important to note, however, that nonlytic strains of NDV can make infectious progeny viruses in some types of nonhuman cells (e.g., chicken embryo cells), Reviewed in [14,19,25,26,33] thereby allowing these strains to be maintained.

Another major difference between lytic strains and nonlytic strains is that, although they both have the potential to kill infected cells, the mechanisms by which they accomplish this result are different. The production of infectious progeny virus particles by lytic strains gives them the ability to kill host cells fairly quickly. The budding of progeny viruses that contain activated hemagglutinin-neuraminidase and fusion protein molecules in their outer coats causes the plasma membrane of NDV-infected cells to fuse with the plasma membrane of adjacent cells, leading to the production of large, inviable fused cells known as syncytia.[13] Reviewed in [14,19,27] The more efficiently a lytic strain can replicate inside a host cell, the more quickly it can kill that cell. The preferential killing of cancer cells by a lytic virus is known as oncolysis; thus, lytic strains of NDV are also called oncolytic strains. In contrast, nonlytic strains of NDV kill infected cells more slowly, with death apparently the result of viral disruption of normal host cell metabolism.[35] Reviewed in [33]

As indicated previously, both lytic strains and nonlytic strains have been investigated for their anticancer potential. In fact, the major differences between the 2 strain types have been exploited to develop 3 different approaches to cancer therapy:

1. The infection of cancer patients with a lytic strain of NDV.
2. The use of oncolysates, i.e., preparations containing plasma membrane fragments from NDV-infected cancer calls, as anticancer vaccines.
3. The use of intact cancer cells infected with a nonlytic strain of NDV as whole cell vaccines.

One proposed advantage of the first approach is that virus replication may allow the spread of cytotoxic viruses to every cancer cell in the body; Reviewed in [9,31] however, the production of virus-neutralizing antibodies by the immune system might limit this possibility. Reviewed in [7,9,14,27] The rationale for the second and third approaches is that tumor-specific antigens (i.e., proteins or other molecules that are generally located in the plasma membrane of cancer cells and that are either unique to cancer cells or much more abundant in them) may be better recognized by the immune system if they are associated with virus antigens (i.e., virus proteins that have been inserted into the plasma membrane of host cells). Reviewed in [9,13,14,25,29,31,36-42] If this enhanced recognition takes place, then it may increase the chance that cancer cells, whether they are virus infected or not, will be recognized as foreign by the immune system and be destroyed. Reviewed in [9,13,25,41,42]

The principal developers of the third approach have stated that whole cell vaccines can stimulate the immune system better than oncolysates, Reviewed in [19,25,26,34,35,37,40,43-45] and that cells infected with a nonlytic strain of NDV will remain intact in the body long enough to generate these more effective immune responses.[35] Reviewed in [33] It should be noted that the cancer cells used in the third approach are treated with enough gamma radiation to prevent further cell division, but not enough to cause cell death, either before or after they are infected with the nonlytic virus.[43,44,46-52] Reviewed in [14] This precaution ensures that patients are not given a vaccine that contains actively proliferating cancer cells.

Either a patient’s own cancer cells (i.e., autologous cells) or cells from another patient with the same type of cancer (i.e., allogeneic cells) can be used to make oncolysates and whole cell vaccines. It is important to note that immune system responses similar to those obtained with oncolysates and whole cell vaccines may occur in patients infected with a lytic strain of NDV and that these responses would be expected to contribute to any observed anticancer effect.

To conduct human studies with viruses, vaccines, or other biological materials in the United States, researchers must file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA). Biological materials and drugs have been held to similar safety and effectiveness standards since 1972. In an IND application, researchers must provide safety and toxicity data from laboratory and animal studies to justify the dose, the route, and the schedule of administration to be used in the proposed clinical studies. Among the safety issues to be addressed, researchers must demonstrate an absence of harmful contaminants. Most human studies of NDV as an anticancer agent have taken place outside the United States; therefore, they have not required an IND. At present, at least 1 group of U.S. investigators has filed an IND application to study NDV as an anticancer treatment.[53] It should be noted that the FDA has not approved the use of NDV to treat any medical condition.

The NDV strains that have been evaluated most widely for the treatment of cancer are 73-T, MTH-68, and Ulster.[1,7,12,36,39,43,44,46-52,54-67] Reviewed in [23,45,68] Strain 73-T is lytic, and Ulster is nonlytic. Strain MTH-68 has not been classified, but it is assumed to be lytic.[1,7,60] Reviewed in [23,69,70] All 3 strains have shown little or no evidence of neurotropism (i.e., an ability to replicate efficiently in normal nerve cells or normal neural tissue).

In animal studies, NDV infection has been accomplished by intratumoral,[10,11,13,24,25] Reviewed in [33] intraperitoneal,[24,25,71] Reviewed in [33] intravenous,[33] intramuscular,[37] or subcutaneous [37] injection. NDV-infected, whole cell vaccines have been given to animals by intraperitoneal,[40] intradermal,[41] Reviewed in [33] or subcutaneous injection, Reviewed in [33] or by a combination of subcutaneous and intramuscular injection.[37,72]

In human studies, NDV oncolysates have been administered by subcutaneous [12,36,39,54,57,59,61-64] or intradermal [56,58] injection. NDV-infected, whole cell vaccines have been administered by intradermal injection only.[43,44,46-52,65-67] In cases where patients have been infected with a lytic strain of NDV, intratumoral,[21] intravenous,[1,53,60,73] or intramuscular [55] injection has been used, as well as inhalation [1,7] and direct injection into the colon (i.e., via a colostomy opening).[1] In some instances, cytokine treatment has been combined with NDV therapy.[39,46,47,50,56,58,59,64]

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Glossary Terms

Taken from different individuals of the same species. Also called allogenic.

A substance that causes the immune system to make a specific immune response.

Taken from an individual's own tissues, cells, or DNA.

Pertaining to biology or to life and living things. In medicine, refers to a substance made from a living organism or its products. Biologicals may be used to prevent, diagnose, treat or relieve of symptoms of a disease. For example, antibodies, interleukins, and vaccines are biologicals. Biological also refers to parents and children who are related by blood.

A term for diseases in which abnormal cells divide without control. Cancer cells can invade nearby tissues and can spread to other parts of the body through the blood and lymph systems. There are several main types of cancer. Carcinoma is cancer that begins in the skin or in tissues that line or cover internal organs. Sarcoma is cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the blood. Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system. Central nervous system cancers are cancers that begin in the tissues of the brain and spinal cord.

The individual unit that makes up the tissues of the body. All living things are made up of one or more cells.

A type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis, or treatment of a disease. Also called clinical trial.

The longest part of the large intestine, which is a tube-like organ connected to the small intestine at one end and the anus at the other. The colon removes water and some nutrients and electrolytes from partially digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus.

An opening into the colon from the outside of the body. A colostomy provides a new path for waste material to leave the body after part of the colon has been removed.

Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices generally are not considered standard medical approaches. Standard treatments go through a long and careful research process to prove they are safe and effective, but less is known about most types of CAM. CAM may include dietary supplements, megadose vitamins, herbal preparations, special teas, acupuncture, massage therapy, magnet therapy, spiritual healing, and meditation. Also called CAM.

A membrane that lines the inner surface of the eyelid and also covers the front part of the eye. Conjunctivitis is inflammation of the conjunctiva.

A substance that is made by cells of the immune system. Some cytokines can boost the immune response and others can suppress it. Cytokines can also be made in the laboratory by recombinant DNA technology and used in the treatment of various diseases, including cancer.

The fluid inside a cell but outside the cell's nucleus. Most chemical reactions in a cell take place in the cytoplasm.

Cell-killing.

The molecules inside cells that carry genetic information and pass it from one generation to the next. Also called deoxyribonucleic acid.

The amount of medicine taken, or radiation given, at one time.

Early stage in the development of a plant or an animal. In vertebrate animals (have a backbone or spinal column), this stage lasts from shortly after fertilization until all major body parts appear. In particular, in humans, this stage lasts from about 2 weeks after fertilization until the end of the seventh or eighth week of pregnancy.

A virus that has an outer wrapping or envelope. This envelope comes from the infected cell, or host, in a process called "budding off." During the budding process, newly formed virus particles become "enveloped" or wrapped in an outer coat that is made from a small piece of the cell's plasma membrane. The envelope may play a role in helping a virus survive and infect other cells.

An agency in the U.S. federal government whose mission is to protect public health by making sure that food, cosmetics, and nutritional supplements are safe to use and truthfully labeled. The Food and Drug Administration also makes sure that drugs, medical devices, and equipment are safe and effective, and that blood for transfusions and transplant tissue are safe. Also called FDA.

A protein made from a fusion gene, which is created by joining parts of two different genes. Fusion genes may occur naturally in the body by transfer of DNA between chromosomes. For example, the BCR-ABL gene found in some types of leukemia is a fusion gene that makes the BCR-ABL fusion protein. Fusion genes and proteins can also be made in the laboratory by combining genes or parts of genes from the same or different organisms.

A type of radiation therapy that uses gamma radiation. Gamma radiation is a type of high-energy radiation that is different from x-rays.

A complex molecule that contains both lipids (fats) and carbohydrates (sugars) and is found in the plasma (outer) membrane of many kinds of cells. Several different types of gangliosides have been identified.

The stomach and intestines. The gastrointestinal tract is part of the digestive system, which also includes the salivary glands, mouth, esophagus, liver, pancreas, gallbladder, and rectum.

Inherited; having to do with information that is passed from parents to offspring through genes in sperm and egg cells.

The complete genetic material of an organism.

A protein found in the outer coat of paramyxoviruses. This protein helps virus particles bind to cells, making infection easier.

A cell that is infected by a virus or another type of microorganism.

The complex group of organs and cells that defends the body against infections and other diseases.

Invasion and multiplication of germs in the body. Infections can occur in any part of the body and can spread throughout the body. The germs may be bacteria, viruses, yeast, or fungi. They can cause a fever and other problems, depending on where the infection occurs. When the body’s natural defense system is strong, it can often fight the germs and prevent infection. Some cancer treatments can weaken the natural defense system.

Redness, swelling, pain, and/or a feeling of heat in an area of the body. This is a protective reaction to injury, disease, or irritation of the tissues.

In medicine, refers to the act of taking a substance into the body by breathing.

Within the skin. Also called intracutaneous.

Within or into muscle. Also called IM.

Within the peritoneal cavity (the area that contains the abdominal organs). Also called IP.

Within a tumor.

Into or within a vein. Intravenous usually refers to a way of giving a drug or other substance through a needle or tube inserted into a vein. Also called I.V..

In clinical trials, refers to a drug (including a new drug, dose, combination, or route of administration) or procedure that has undergone basic laboratory testing and received approval from the U.S. Food and Drug Administration (FDA) to be tested in human subjects. A drug or procedure may be approved by the FDA for use in one disease or condition, but be considered investigational in other diseases or conditions. Also called experimental.

A researcher in a clinical trial or clinical study.

Not able to survive.

Research done in a laboratory. These studies may use test tubes or animals to find out if a drug, procedure, or treatment is likely to be useful. Laboratory studies take place before any testing is done in humans.

Inflammation of the larynx.

Having to do with lysis. In biology, lysis refers to the disintegration of a cell by disruption of its plasma membrane. Lysis can be caused by chemical or physical means (e.g., high-energy sound waves) or by a virus infection.

A very thin layer of tissue that covers a surface.

The smallest particle of a substance that has all of the physical and chemical properties of that substance. Molecules are made up of one or more atoms. If they contain more than one atom, the atoms can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms.

Having to do with nerves or the nervous system, including the brain and the spinal cord.

An ability to invade and live in neural tissue. This term is usually used to describe the ability of viruses to infect nerve tissue.

A bird virus that is being studied in the treatment of cancer. It may be used to kill cancer cells directly, or it may be given as a cancer vaccine to stimulate the body’s immune system. Newcastle disease virus is a type of biological response modifier and vaccine therapy. Also called NDV.

In biology, refers to viruses that do not kill infected cells by disrupting their plasma membranes.

Not harmful or destructive.

An extract made from cancer cells.

The lysis (breakdown) of cancer cells. This can be caused by chemical or physical means (for example, strong detergents or high-energy sound waves) or by infection with a strain of virus that can lyse cells.

A type of virus that has hemagglutinin-neuraminidase proteins in the outer coat and RNA as the genetic material. Measles (rubeola) virus, mumps virus, and Newcastle disease virus are paramyxoviruses.

The outer membrane of a cell.

Research using animals to find out if a drug, procedure, or treatment is likely to be useful. Preclinical studies take place before any testing in humans is done.

Offspring; the product of reproduction or replication.

Multiplying or increasing in number. In biology, cell proliferation occurs by a process known as cell division.

A molecule made up of amino acids that are needed for the body to function properly. Proteins are the basis of body structures such as skin and hair and of substances such as enzymes, cytokines, and antibodies.

To make a copy or duplicate of something.

In biology, refers to the reproduction cycle of viruses. A repliction cycle begins with the infection of a host cell and ends with the release of mature progeny virus particles.

The organs that are involved in breathing. These include the nose, throat, larynx, trachea, bronchi, and lungs. Also called respiratory system.

In medicine, an improvement related to treatment.

One of the two types of nucleic acids found in all cells. In the cell, RNA is made from DNA (the other type of nucleic acid), and proteins are made from RNA. Also called ribonucleic acid.

Any of a group of simple sugar molecules.

Beneath the skin.

A large cell-like structure formed by the joining together of two or more cells. The plural is syncytia.

Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects.

A protein or other molecule that is unique to cancer cells or is much more abundant in them. These molecules are usually found in the plasma (outer) membrane, and they are thought to be potential targets for immunotherapy or other types of anticancer treatment.

A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. A vaccine can help the body recognize and destroy cancer cells or microorganisms.

Having to do with a virus.

Refers to the ability of a virus or a bacterium to cause damage to its host.

An antibody that binds to a virus and interferes with its ability to infect a cell.

Vaccine made from whole tumor cells that have been changed in the laboratory.