The immune system is the body’s defense against invasion by bacteria, viruses and other foreign substances not normally found in the body. When germs try to use the body for harm, the immune system’s organs, cells and beneficial substances work not only to prevent them from entering in the first place, but to kill them if they do get in. A substance which causes the immune system to react and attack is called an antigen, and the response the antigen solicits can destroy both the antigen itself and anything attached to it, such as germs or cancer cells. Unfortunately, the immune system is better equipped to identify germs because their cells are considerably different from normal body cells, whereas the difference between cancer cells and normal cells may be less clearly defined. Even if the immune system does recognize the cancer cells, its response may not be strong enough to destroy them. It is also possible that the cancer cells give off substances that keep the immune system from doing its work properly.
There is some evidence that mesothelioma cells are susceptible to immune mechanisms, and that the potential exists for mesothelioma to be successfully treated through immunological means. Most studies to date, however, have focused on single-agent therapy and because the tumor has several mechanisms which allow it to evade recognition by the immune system, limited results have been achieved thus far. It is hoped that by combining surgery, chemotherapy and/or radiation therapy with immunotherapy, that results will ultimately improve.
When a person has mesothelioma, his or her tumor cells overexpress a protein called mesothelin. This protein can be a target for the immune system (naturally or supplemented through immunotherapy). Mesothelin is in the membrane of the cells and called a “glycosyl phosphatidylinositol-anchored glycoprotein”. Several approaches to immunotherapy treatment of mesothelioma are under investigation.
Types of immunotherapies may include:
- Active immunotherapies or those which stimulate the body’s own defenses to fight disease.
- Passive immunotherapies or those which use immune system components created outside the body.
- Non-specific immunotherapies and adjuvants or those which stimulate the body’s immune system in very general ways, but may still show activity against cancer cells.
Cancer vaccines are examples of active immunotherapies, and are for the most part, still experimental. When most of us think of vaccines, we imagine those we had as children that protected us from measles or the mumps. These types of vaccines used weakened or killed viruses that stimulated a response in the body and alerted the body to invasion by these viruses in the future. The purpose of cancer vaccines is to attack disease that already exists in the body.
Some of the vaccines currently being studied are:
These vaccines contain cancer cells removed from the patient during surgery. The cells are then treated in the laboratory so they can not proliferate further, and are altered through the addition of chemicals or new genes so they are more recognizable to the immune system. The cells are then injected back into the patient, with the goal that the immune system will recognize the antigens on the altered cells and attack any remaining cells with those antigens.
There are two basic types of tumor cell vaccines, autologous (created from killed tumor cells of the same person into which they will later be reinjected), and allogenic (grown from a stock of tumor cells removed from other patients) and then injected into a new patient. In some cases, these vaccines are given in conjunction with adjuvant treatments to boost the immune system.
These vaccines boost the immune system by using a limited number of antigens as opposed to using whole tumor cells that contain thousands of antigens. These antigens are normally proteins, called peptides. Antigen vaccines may be specific to a certain type of cancer, but are not unique to an individual patient, therefore, since mass production of antigens is now possible, vaccines can be given to a larger patient population.
Dendritic Cell Vaccines
These vaccines, like tumor cell vaccines, must be made individually for a particular patient. Doctors remove some dendritic cells from the blood, and treat them in the laboratory to encourage them to multiply, creating a larger number of cells. The cells are then exposed to antigens in a dish or are genetically modified so they create their own antigens. The dendritic cells are then reinjected into the patient with the hope that the immune system will recognize and attack any cancer cells with tumor antigens on their surface.
When tumor cells or antigens are injected into a patient, the immune system recognizes them as invaders and mounts a response to destroy them. Unfortunately, after this initial assault, the immune system may revert to its pre-vaccine state. The substance in cells that contains the genetic code for proteins made by the cells is called DNA. By removing cells from the body, treating them with DNA that codes for a specific antigen and then reinjecting them into the body, it is possible that the altered cells would continue to produce antigens on an ongoing basis.
Vectors are structures such as bacteria and viruses that may be used to get antigens or DNA into the body. These vectors are treated in the laboratory prior to being given to the patient to be sure they are no longer capable of causing illness on their own. Vector-based vaccines are able to deliver more than one antigen at a time, therefore, the chances of the immune system reacting to the antigens are increased.
Non-vaccine Active Immunotherapies
There are other non-vaccine active immunotherapies under investigation in the clinical trial system at this time. These differ from vaccines in that they are therapies that try to boost specific parts of the immune system rather than to try to get the immune system to react to specific antigens. While some of these treatments have shown promising results in animal studies, testing on humans has not been as effective. Nonetheless, researchers continue to test new methods to improve results.
Monoclonal antibody therapy is the most widely used form of immunotherapy for cancer available today. This is a passive immunotherapy, meaning it uses antibodies created in the laboratory rather than by the patient’s own immune system, and does not require the immune system itself to actively fight the cancer. Research on monoclonal antibodies (MoAbs or MAbs) has been ongoing for a number of years, and there are currently clinical trials in progress for almost every type of cancer. In recent years, the Food and Drug Administration (FDA) has approved many monoclonal antibodies, some of the more well known being Avastin (bevacizumab) for colon cancer and Herceptin (trastuzumab) for breast cancer.
The two types of monoclonal antibodies used for cancer treatment are: Naked monoclonal antibodies (those with no drug or radioactive material attached to them) and Conjugated monoclonal antibodies (those joined to chemotherapy drugs, radioactive particles or toxins. Naked monoclonal antibodies are those most widely used at this time, and although they were originally recommended primarily after other therapies had failed, they are now being used as an earlier treatment option.
Monoclonal antibodies are administered intravenously just as most chemotherapies, however, the side effects of naked Mabs are usually relatively mild, and are related to allergic-type reactions, most often when the drug is first given. Other possible side effects may include chills, fever, headache, nausea, vomiting, diarrhea and rash. Patients who are candidates for monoclonal antibody therapy should discuss potential benefits, risks and side effects with their doctors.
Conjugated monoclonal antibodies are more potent than naked monoclonal antibodies, but also carry a higher risk of side effects because they are joined to drugs, radioactive substances or toxins. They are used as a method of delivering these substances directly to the cancer cells, and circulate throughout the body until determining where they are needed most.
Nonspecific Immunotherapies and Adjuvants
Nonspecific immunotherapies may be given alone, while others are used as adjuvants, meaning they are given in combination with another treatment in order to boost immune system function and improve the effectiveness of the primary treatment.
Some types of nonspecific immunotherapies and adjuvants may include:
Cytokines are chemicals produced primarily by white blood cells. They provide signals to regulate the immunological aspects of both cell growth and function. Cytokines include the interleukins, interferons, tumor necrosis factors, erythropoitin and colony-stimulating factors. Currently, cytokines are being used to help lessen the effects of traditional treatments such as chemotherapy, however, man-made cytokines are also being used to help boost the immune system and as adjuvant treatment with tumor vaccines. Cytokines are administered by injection, either into a vein or muscle, or under the skin.
Interleukins are a group of cytokines that enable communication between white blood cells active in the cell-mediated immune response. Interleukin-2 (IL-2) was the first of this group to be approved by the FDA in 1992, and since that time, other interleukins, such as IL-7, IL-12 and IL-21 have been studied in the treatment of cancer, both as single agents and as adjuvants.
Interferons are a group of cytokines that help the body to resist virus infections and cancer. There are three types of interferons which have been approved by the FDA, however, only Interferon-alpha (IFN-alpha) is used to treat cancer. Interferons may work by slowing the growth of cancer cells, by slowing the growth of blood flow to the tumor (angiogenesis) and by causing the cancer cells to produce more antigens which makes them easier for the body’s immune system to recognize and destroy.
Granulocyte-macrophage colony-stimulating factor (GM-CSF)
GM-CSF is a cytokine/growth factor that causes bone marrow to create more immune system cells and blood cells. The man-made version, sargramostim, is sometimes used to increase white cell counts after chemotherapy treatments. GM-CSF is also being studied as a nonspecific immunotherapy and as an adjuvant with other immunotherapies for the treatment of cancer.