Immunotherapy, which is also called biological therapy or biotherapy, is a treatment that uses certain characteristics of the body’s immune system to fight disease. As we will see later, the basic idea of cancer immunotherapy is to try to get the immune system to react to the tumor’s cancer cells as if they are foreign. The use of immunotherapy as a cancer treatment is not new. Dr. Herberman notes that, "For over 100 years, immunologists have been intrigued by the concept that tumor cells are foreign to the local host and that the immune response has the potential to recognize the key difference(s) and reject the tumor cells."1 Drs. Brown and Kirkwood point out that immunology has, "burgeoned from the esoteric specialty of a small body of individuals into an immense academic discipline whose basic doctrines permeate all aspects of clinical medicine."2 Although immunotherapy is sometimes used by itself, it is typically used as an adjuvant to another primary therapy, i.e., along with or after the primary therapy, to add to the anticancer effects of the primary therapy.
The Immune System
The immune system defends the body against infection, disease and foreign substances. It is made up of many organs and cells. An antigen is a substance that causes the immune system to make a specific response, called the immune response. Viruses, bacteria, germs, and parasites contain substances that are not normally present in the body and thus cause an immune response. The immune response can lead to destruction of the antigen and anything it is part of or to which it is attached.
Several different types of cells are involved in the immune system’s response to an antigen. Among the cells are antigen-presenting cells (APCs), lymphocytes, and granulocytes. Among the APCs are monocytes and macrophages and dendritic cells. Among the lymphocytes cells are B cells (B lymphocytes), T cells (T lymphocytes), Killer T cells, and Helper T cells.
The National Cancer Institute (NCI) has a good tutorial on "The Immune System." NCI's "Cancer Vaccine Primer" and the companion article, "NCI Pursues Vaccine to Prevent and Treat Cancer" are also worth reading.
Vaccine Therapy and Antibody Therapy
Cancer cells have substances on their outer surfaces that can act as antigens and thus "mark" the cells as different or abnormal. Viruses, bacteria, and parasites have cells that are substantially different from normal human cells because they are truly foreign to the body and are detected by the immune system. However, the differences between cancer cells and normal human cells may be more difficult for the immune system to detect. Cancer immunotherapies are designed to help the immune system recognize cancer cells and/or to strengthen the immune response to the cancer cells and thus destroy the cancer. The cancer cells' antigens may not be different enough from those of normal cells to cause an immune reaction; thus, the immune system may not recognize the cancer cells as foreign. The immune system may recognize the cancer cells’ antigens, but the immune response may not be strong enough to destroy the cancer. Additionally, some cancer cells themselves may also give off substances that prevent the immune system from responding properly.
There are two broad classes of immunotherapies, active immunotherapy and passive immunotherapy. Active immunotherapies stimulate the body’s own immune system to fight the disease. Passive immunotherapies do not rely on the immune system to attack the disease; instead, they use immune system components (such as antibodies) that are created outside of the body to fight the disease. These two approaches are also called vaccine therapy and antibody therapy respectively. In vaccine therapy, or active therapy, the patient is given a vaccine that should stimulate the immune system to attack the cancer. In antibody therapy, or passive therapy, the patient is given antibodies that will hopefully target the cancer but leave the non-cancerous cells alone. The problem with both approaches is finding substances that the immune system can target (antigens) which are only present on the cancer cells and not on normal cells. Sometimes vaccines combined with nonspecific immunotherapy, using additional substances or cells called adjuvants in order to boost the immune system’s response. Doctors may employ two or more of these immunotherapy options together.
An antibody is a protein made by certain white blood cells in response to the presence of an antigen. Antibodies bind to antigens to help destroy the antigen. Each antibody can only bind to a specific antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for other cells to destroy the antigen.
Cancer vaccines contain cancer cells, parts of cells, or pure antigens that increase the immune response against cancer cells that are already present in the body. They are considered active immunotherapies since they are meant to trigger your own immune system to respond. They are considered specific because they do not result in a generalized immune system response. They cause the immune system to produce antibodies to one or several specific antigens, and/or to produce Killer T cells to attack cancer cells that have specific antigens.
There are several different types of vaccines; among them are tumor cell vaccines, dendritic cell vaccines, antigen vaccines, anti-idiotype vaccines, and DNA vaccines. I will only briefly discuss tumor cell vaccines in Q&A response column. Tumor cell vaccines use cancer cells that are removed from the patient during surgery. The tumor cells are then killed so they cannot form more tumors. The tumor cells may be modified with chemicals or genes, or mixed with other substances known to increase the immune response in an attempt to improve the effectiveness of the vaccine. The tumor cells are the injected back into the patient. The antigens on the cells are recognized and attacked by the immune system.
The two basic types of tumor cell vaccines are autologous and allogeneic. An autologous vaccine is made from tumor cells taken from the patient that will receive them. An allogeneic vaccine uses cells of a particular cancer type that originally came from someone other than the patient that will receive them. The cells are often "grown" in a lab from a "stock" of cancer cells kept for this purpose.
There are several problems with tumor cell vaccines:
- the difficulty and cost of creating a new, unique vaccine for each cancer patient
- the mutations (changes) in the cancer cells can result in the vaccine becoming less effective over time
- When cancer metastasizes, the new tumor sites can have cells with slightly different antigens; thus a vaccine made from one tumor site might not be effective against the other tumor sites.
There are many vaccine-based clinical trials underway for a wide variety of cancers, including sarcomas. Some of them are currently recruiting patients and can be viewed here.
In monoclonal antibody therapy, large quantities of antibodies are produced in the lab outside the body rather than inside the body by the immune system. Since the immune system does not take an "active" role in fighting the cancer in antibody therapy, it can be used even in patients with a weakened immune system. Researchers can make monoclonal antibodies that react with specific antigens on certain types of cancer cells. As researchers discover more specific cancer-associated antigens, they will be able to direct monoclonal antibodies against more and more cancers.
Monoclonal antibodies are laboratory-produced antibodies that can locate and bind to specific cancer cells anywhere in the body. Each monoclonal antibody recognizes a different protein on specific cancer cells. Monoclonal antibodies are used in cancer detection as well as in cancer therapy. They can be used alone or to deliver drugs, toxins, or radioactive material directly to a tumor.
There are two types of monoclonal antibodies that are used in cancer treatments:
- Monoclonal antibodies without any drug or radioactive material attached to them: These are referred to as "naked" monoclonal antibodies. Naked antibodies attach themselves to specific antigens on cancer cells.
- Monoclonal antibodies joined to a chemotherapy drug, radioactive particle, or a toxin (a substance that poisons cells): These are referred to as "conjugated", "tagged," "labeled," or "loaded" monoclonal antibodies.
There are clinical trials of monoclonal antibodies in progress for a wide range of cancers, including non-Hodgkin’s lymphoma, breast cancer, acute myelogenous leukemia, chronic lymphocytic leukemia, colorectal cancer and sarcomas. Researchers at St. Jude Children’s Research Hospital and other institutions are studying a drug called Herceptin® to treat recurrent or metastasized osteosarcoma. In this clinical trial, Herceptin® is given by vein. Some of the current monoclonal antibodies being studied in conjunction with sarcomas are: MAb, AME, Onyvax-105, bevacizumab, and trastuzumab. Another, TriGem, has demonstrated the ability to induce an immune response to the GD2 ganglioside. This is an antigen that is present on a number of tumor types, among them are melanoma, small cell lung cancer, neuroblastoma and sarcoma. To view open clinical trials that involve monoclonal antibodies, click here.