Immunotherapy, Biologic Therapy, and Biotherapy
Updated: Wednesday, June 15, 2005 12:04:57 PM
IMMUNOTHERAPY, BIOLOGIC THERAPY, AND BIOTHERAPY: These three terms are a broad category which involve treatment with agents derived from biologic sources, or which provoke the biologic response in humans. The immune system relies upon the antigen-antibody response. During this description, think of a battle. Antigens, foreign invaders, are proteins with unique properties which make them recognizable as "different" to antibodies, the defenders of the castle, which are a natural part of our immune system. Antigens can be germs, viruses, pollens, or even cells from another person. Cancer cells have antigens which are not found on normal cells. Our bodies see these antigens as abnormal and produce antibodies specific to those antigens. Think of it as a "lock and key" mechanism, in which a specific antibody targets, or locks on to, a specific antigen. Antibodies can't attack the cell, but only mark it for destruction by the immune system (the body's soldiers) later. Antibodies are like buglers calling the soldiers to attack. However, Antibody A only recognizes Enemy A (antigen A), and does not know that Antigen D, P, or L are enemies. Remember, specific antibodies only fight their matching, or targeted, antigens.
Early clinical trials show that these agents are fairly non-toxic and work the best on adenocarcinomas (a cell type common in ovarian cancer). Immunotherapy is thought to be most effective just after surgery, chemotherapy and/or radiation have done their job, leaving only small amounts of residual tumor (microscopic, or not visible on CT scans, x-rays, MRI's, etc.). They are also considered to be most effective when the body's own immune system is at its peak, such as immediately after diagnosis, first surgery, or just after the first indication of recurrence.
Immune cells are designed to identify, surround, and digest the enemy. The most active immune cells are the various types of lymphocytes (white blood cells), which are called T cells, NK cells, and B cells.These cells are circulating in the blood stream all the time, searching for their matching antigen-antibody substances. T cells identify the substance as an invader and multiply to produce cytokines, or cell killers, called lymphokines. Then the lymphokines trumpet the news and call/mobilize other cells to destroy the targeted cells. NK (natural killer) cells will attack any target they can find. B cells produce the specific antibodies, the chemical weapons, as well as plasma cells, which are factories that produce more of the identical antibodies. Some lymphocytes become memory cells, remembering to destroy the antigen the next time that specific cell meets with the antigen. However, memory cells get a little foggy over time and must be shown pictures of the enemy periodically. (Just as an aside, research shows that stress reduces NK and T cell activity.)
Some of the categories of biological response modifiers are cytokines (mentioned above). Cytokines agents are interferons, the interleukins, tumor necrosis factor (TNF), hematopietic growth factor (HGF), monoclonal antibodies (Mabs), and the retinoids. Biologic response modifiers are considered to be a non-specific approach, and therefore are not as useful alone as in combination with other things. Using them alone is comparable to throwing rocks at the enemy with your eyes closed. Combinations are considered more effective. Antibodies can be linked with drugs, toxins, viruses, or radioactive drugs, and then sent out to search for the targeted antigens on cancer cells. Or the lymphokine can be linked with a toxin and cells which have antigens for that particular lymphokine. Unfortunately, all of these agents seem to have unpleasant common side effects of flu-like symptoms, or allergy symptoms (rash, itching, hives, etc.).
The word interleukin means "between leukocytes" (white blood cells). These hormonal proteins act as messengers to regulate the action of other leukocytes. They cause reactions in other hormonally regulated systems of the body. Interleukins are named according to their protein sequence (their place in line), and so get wonderfully innovative names like IL-2 or IL-9, etc. Interleukins have been used with both blood and solid tumors. IL-2 seems to have been the most commonly studied, but recently I have noticed ovca research using IL-12.
Retinoids are natural or man-made forms of vitamin A, which are vital to cell growth and reproduction, as well as to the immune system. These are the most frequently used in chemoprevention (cancer prevention) clinical trials, but recently retinoids are entering the area of "treatment" clinical trials. They may have added side effects of changing visual acuity. (Remember, your mother always told you to eat carrots for good vision, and carrots are very high in retinoids!)
Interferons are a group of hormones which can slow cell growth and influence the immune system, are active against viruses, suppress oncogenes, and inhibit angiogenesis. They seem to work better against blood cancers than solid cancers (ovarian cancer is considered a solid tumor), but clinical trials in ovca are underway at many major cancer centers using interferons. The three groups of interferons are alpha, beta, and gamma, but alpha is most often used to treat cancer.
We are all probably familiar with the hormone-like proteins regulating blood cell growth called hematopoetic growth factor, or HGF. These usually only effect the growth of a specific blood cell. Some work on only a specific type of blood cell (such as the red blood cells), while others work on several different types of blood cells. For example, I suspect most of us have already benefited from the HGF known as Neupogen, or GM-CSF (short for granulocyte-macrophage colony stimulating factor). Neupogen allows faster recovery of the white blood cell count after higher doses of chemotherapy. Therefore, some HGF's are considered supportive. These have the added side effect of bone pain because they tell the bone marrow to "get busy."
Monoclonal antibodies (MAbs) are antibodies mass produced in a lab. Usually, a mouse is injected with the target antigen and then the B cell anti-body producing plasma cells are collected from the mouse. Then identical (monoclonal) antibodies are grown in the lab. Monoclonal antibodies work the same way as other antibody-antigen "lock and key" mechanisms. They attach to their specific antigen and then call other immune system players to attack the cancer cell, but not any other cell. Monoclonal antibodies may be used to strengthen the immune system response, to attack residual cancer cells left after other treatments, to act as a vaccine, and to deliver toxins (such as anti-cancer drugs, chemo, radioactive substances, and biological response modifiers) directly to the tumor with less harm to normal cells. Side effects with monoclonal antibodies are usually milder than chemo, and may be limited to the tumor site. Unfortunately, the human immune system eventually inactivates the mouse monoclonal antibodies. Scientists are working on disguising the mouse antibodies to make them even more receptive to our antibodies. Herceptin is a monoclonal antibody used for breast cancers which over-express Her-2/neu gene. Herceptin, an anti-Her-2/neu is marketed by Genentech (888-435-4372) and their web site [http://www.genentech.com] (click "news," click "most recent press releases," then "9/2/98." However, the drug is so rare that it is only available via a monthly lottery system. I have heard of some very small phase I ovca clinical trials using Herceptin.
Monoclonal antibodies are passive Immunotherapy--the antibodies are made outside the body and given to the patient. Vaccines are considered active Immunotherapy agents because the body is stimulated to make its own antibodies. Traditionally, most vaccines are created when a small dose of the infectious agent (the antigen) is given to a person to establish immunity. It is like giving the immune system a sneak peak at the enemy, giving it a head start in preparing its defenses (antibodies). In cancer therapy, vaccines are made when cells are grown in the lab, loaded with the cancer antigens, used to turn on the lymphocytes in the lab, and then given as a vaccine to immunize people, stimulating their own defenses. Most vaccines must be made from the person's own cancer specific tumor to be effective and will not work if made from another person's tumor. (Remember the "lock and key" mechanism?) In an ovca clinical trial at Thomas Jefferson University in Philadelphia, the initial aggressive de-bulking surgery must be done there in order to properly obtain the cancer cells necessary to grow the vaccine. Then, traditional chemo treatments are given to further reduce the number of cancer cells before the patients get a series of vaccine shots. A vaccine trial to prevent other recurrences is the Le Y-KLH (Lewis-Y) at Memorial Sloan-Kettering in NYC. Others are vaccines made of tumor cells which have been irradiated to prevent growth, and then have a cytokine added before being injected into the person's skin. Still others use a vector (carries the antigen), which is then injected directly into the tumor where the tumor cells will produce more antigens.