Experimental Mesothelioma Treatments : Immunotherapy

Immunotherapy is treatment that uses certain parts of the immune system to fight disease, including cancer. This can include stimulating your own immune system to work harder, or using an outside source, such as manmade immune system proteins.

Other terms used to describe immunotherapy include:

- Biologic response modifiers

- Biologic therapy

Some oncologists (cancer doctors) now consider immunotherapy as the fourth way of treating cancer. The 3 most common forms of treatment are:

- Surgery

- Radiation

- Chemotherapy

Immunotherapy is sometimes used by itself, but it is most often used as an adjuvant (along with or after another type of therapy) to add to the anticancer effects of the main therapy.

Although the thought of using your own immune system to fight cancer is appealing, immunotherapy currently has a small role in treating the most common types of cancer. In general, immunotherapy is most likely to be effective when treating small cancers and will probably be less effective for more advanced disease. Researchers, however, have made important progress in this field in the past few years. Many are optimistic that more effective immunotherapies can be developed that will have a greater impact on the outlook for people with cancer.

Types of Immunotherapy

Obviously, some people with functioning immune systems still develop cancer. Sometimes the immune system doesn’t recognize cancer cells as foreign because the cancer cells’ antigens are not different enough from those of normal cells to cause an immune reaction. Or the immune system may recognize cancer cells, but the response may not be strong enough to destroy the cancer. Cancer cells themselves may also give off substances that keep the immune system from doing its job.

Because of this, researchers have designed different types of immunotherapies to help the immune system recognize cancer cells and to strengthen the response so that it will destroy the cancer.

Active immunotherapies stimulate the body’s own immune system to fight the disease. Passive immunotherapies do not rely on the body to attack the disease; instead, they use immune system components (such as antibodies) created outside of the body.

Types of immunotherapies include:

- Cancer vaccines (active specific immunotherapies)

- Monoclonal antibody therapy (passive immunotherapies)

- Nonspecific immunotherapies and adjuvants

Sometimes, doctors will use two or more of these immunotherapy options together. Some tumors are more effectively attacked by one kind of immune system cell than another, so doctors and researchers use that knowledge when designing and applying immunotherapies.

Cancer Vaccines (Active Specific Immunotherapies)

Most of us are familiar with vaccines that use weakened or killed viruses, bacteria, or other germs, which are given to healthy people to prevent infectious diseases, such as measles.

A cancer vaccine contains cancer cells, parts of cells, or pure antigens. The vaccine increases the immune response against cancer cells that are already present in the body.

Cancer vaccines are considered active immunotherapies because substances injected into the body are meant to trigger your own immune system to respond.

They are specific because they don’t bring about a generalized immune response.

Cancer vaccines 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 those antigens.

Vaccines may also be combined with nonspecific immunotherapy, using additional substances or cells called adjuvants to boost the immune response.

While cancer vaccines have shown some promise in early clinical trials, as of yet none have been approved in the US for use against cancer. 

Tumor Cell Vaccines

Tumor cell vaccines use cancer cells removed during surgery. The tumor cells are killed, usually by radiation, so they cannot form more tumors. They are then injected into the patient.. Antigens on the tumor cell surfaces are still there, and they can stimulate a specific immune system response. As a result, cancer cells carrying these antigens are recognized and attacked.

In some cases, doctors change the tumor cells with chemicals or genes, or mix them with other substances known to increase the immune response. These substances are referred to as nonspecific adjuvants. The general boost they give to the immune system is meant to improve the effectiveness of the vaccine.

Some promising newer versions of these vaccines use tumor cells that are fused to dendritic cells, in the hope of further stimulating the immune system.

One reason for using whole tumor cells in vaccines, instead of individual antigens, is that not all cancer antigens have been identified yet. Using the whole tumor cell may expose the immune system to a large number of important cancer antigens, including some that researchers have not yet recognized.

The two basic kinds of tumor cell vaccines are autologous and allogeneic.

Autologous (pronounced "aw-tall-ah-guss") vaccines: Autologous comes from the Greek words autos (self) and logos (proportion, or part) and means "coming from the self." An autologous tumor cell vaccine is made from killed tumor cells taken from the same person in whom they will later be used. In other words, cells are taken from you (during surgery), the vaccine is made, and the killed cells are injected back into you. Autologous cancer cells may be reinjected shortly after surgery, or they may be grown in the lab or preserved by freezing after being removed, and reinjected later. 

Although autologous tumor cell vaccines remain promising, there are several potential drawbacks:  

- It is difficult and expensive to create a new, unique autologous tumor cell vaccine for each cancer patient.  

- Cancer cells tend to mutate, or change, so an autologous tumor vaccine effective against your cancer cells at first might become less effective later if those cells change.

- Some people have several tumors (the original tumor, and a new tumor or tumors in areas where the cancer has spread). Because cancer cells tend to mutate, or change genetically, each of these tumors can have slightly different antigens. That means an autologous tumor cell vaccine made from one tumor might not be effective against the other tumors.  

- You may not have enough usable cells in the removed tumor to make a vaccine.  

- When your own tumor cells are used to create a vaccine, these cells typically do not cause a strong immune response to begin with and may even give off substances that suppress the immune system. Researchers have sought to overcome this problem by altering the tumor cells before reinjecting them. This may involve treatments with certain chemicals that alter substances on the cell surface, or the addition of genes that instruct the tumor cells to produce new substances that attract immune system cells. Cytokines (natural immune system hormones) that stimulate activity of immune system cells may be able to counteract the actions of the substances tumors give off to suppress the immune system.  

Because of the difficulty in making a new autologous vaccine for every patient, researchers are also looking at ways to create tumor cell vaccines that could work in any patient with a particular kind of cancer. 

Allogeneic (pronounced "allo-jen-ay-ick") vaccines: Allogeneic comes from the Greek words allos (other) and genein (to produce) and means "coming from another patient." These vaccines use cells of a particular cancer type that originally come from someone other than you. The cells are grown in the lab from a stock of cancer cells kept for that purpose. Some allogeneic tumor vaccines use a mixture of cells, originally removed from several patients. The allogeneic cells are killed and are usually injected along with one or more adjuvant substances known to stimulate the growth or activity of immune system cells. 

Tumor cell vaccines are not yet routinely used to treat cancer. They are available in the US at this time only through clinical trials. While the US Food and Drug Administration (FDA) has not yet approved any tumor cell vaccines for general use, they are being studied in clinical trials against several types of cancer, including:  

- Melanom

- Kidney Cancer

- Ovarian Cancer

- Breast Cancer

- Colorectal Cancer

- Lung Cancer

- Lukemia

Dendritic Cell Vaccines

Dendritic cells are specialized antigen-presenting cells that help the immune system to recognize cancer cells. They break down the antigens on the cancer cell surfaces into smaller pieces, then hold out, or "present," those antigen pieces to T cells, making it easier for the immune system cells to react with and attack them.  

Dendritic cells are the most effective antigen-presenting cells now known. They get their name from the Greek word dendron, meaning tree. Their shape resembles that of a tree, with roots and branches spreading out from the main body of the cell. (They should not be confused with dendrites, which are the treelike parts of nerve cells and whose name is derived from the same Greek word.)  

Dendritic cell vaccines, like autologous cell vaccines, are patient-specific and must be made individually for each patient. The process used to create them is involved and expensive: 

Scientists remove some dendritic cells (from the blood) and treat them in the lab to make them reproduce rapidly, creating many more than were withdrawn.  

These dendritic cells are then "taught," in the lab, to recognize cancer antigens. This is done by exposing them to the antigens in a dish, or by genetically modifying them so that they make their own antigens. Some newer studies are even looking at fusing dendritic cells with tumor cells, creating dendritic cells with tumor antigens on their surface.  

The dendritic cells are then injected back into the body.  

The "trained" dendritic cells are better able to help the immune system recognize and destroy cancer cells that have those antigens on them.  

The dendritic cell vaccine approach has shown a great deal of promise in tests done in laboratory animals and in preliminary studies in humans. It is not yet available to the general public but is offered through clinical trials to people with these and other cancers:  

- Prostate Cancer

- Melanoma

- Kidney Cancer

- Colorectal Cancer

- Lung Cancer

- Non-Hodgkin's Lymphoma

Antigen Vaccines

Antigen vaccines stimulate the immune system by using individual antigens, rather than whole tumor cells that contain many thousands of antigens. While antigen vaccines may be specific for a certain type of cancer, they are not made for a specific patient like autologous cell vaccines. 

Scientists have recently determined the genetic codes of many antigens, so they can mass-produce them in the lab. In fact, some antigens can now be produced entirely from man-made chemicals. Scientists can change these antigens to make them more easily recognized by the immune system.  

This new technology means that large amounts of these very specific antigens can now be given to many patients. We know that some antigens cause an immune response in patients with certain cancers. Others produce immune reactions to more than one kind of cancer.  

Often scientists combine several antigens in each vaccine to cause a response to more than one of the antigens that may be present on cancer cells. 

Antigen vaccines are being studied for use against these cancers, among others: 

- Breast Cancer

- Prostate Cancer

- Colorectal Cancer

- Ovarian Cancer

- Melanoma

- Pancreatic Cancer

Anti-Idiotype Vaccines 

Every B lymphocyte or plasma cell that produces antibodies produces only one kind of antibody. The unique part of each type of antibody is called an idiotype. The word idiotype comes from the Greek words idios, meaning one’s own, and typos, meaning type or kind.  

Usually antibodies are thought of only as substances produced when the immune system responds to antigens. But the immune system also produces some antibodies that treat other antibodies like antigens. In other words, sometimes antibodies themselves act as antigens, triggering an immune response. Immunologists believe these antibodies to antibodies are important in regulating the immune system.  

Antibodies and antigens are said to fit together like a lock and key. So, an antibody to a particular idiotype of an antibody (an anti-idiotype) will usually look like the antigen that triggered production of the antibody in the first place (ike using the lock itself to create an extra key). Because the anti-idiotype antibodies look like the antigen, the immune system attacks the anti-idiotypes, along with the antigens themselves, when they are injected into a patient.  

Scientists have learned how to mass-produce these anti-idiotype antibodies. They can be used as part of a cancer-specific vaccine because they look like the antigens originally on the cancer cells in the patient’s body. Therefore they can trigger an immune response against that specific cancer. The whole process is similar, in a way, to making a key by obtaining an impression of the inside of the lock it fits. 

Like antigen vaccines, anti-idiotype vaccines are not unique for each patient. They are currently being tested for use against these types of cancer, among others:  

- Lymphoma

- Melanoma

- Multiple Myeloma

- Breast Cancer

- Lung Cancer

- Colorectal Cancer

Some researchers consider lymphomas to be the most promising targets for anti-idiotype vaccines. This is because all lymphoma cells have unique antigen receptors not present on normal lymphocytes or other normal cells of the body. These unique antigen receptors can be used for preparing lymphoma vaccines. Preliminary studies of B-cell lymphomas have yielded promising results.  

DNA Vaccines

When antigens or anti-idiotypes are injected into the body as a vaccine, they may produce the desired immune response at first but often become less effective over time. This is because antibodies recognize them as foreign and rapidly attach to them, after which immune system cells destroy them. Without any further stimulation, the immune system often returns to its normal (pre-vaccine) state of activity. To get around this, scientists have looked for a way to provide a steady supply of antigens to keep the immune response going. 

DNA (deoxyribonucleic acid) is the material in cells that contains the genetic code for the proteins that cells produce. Scientists are now looking at injecting bits of DNA (instead of certain antigens) that would be taken up by cells and would instruct them to continuously produce the specific antigens (which are proteins). These types of therapies are called DNA vaccines.  

Scientists may also be able to remove cells from the body, treat them with DNA containing instructions for making a particular antigen, and then return them. The altered cells would then produce the antigen on an ongoing basis to keep your immune response strong.  

DNA vaccines are now being studied in clinical trials for use against the following cancers, among others: 

- Melanoma

- Lukemia

- Prostate Cancer

- Head and Neck Cancer

Recombinant DNA technology takes genes from one organism and "splices," or transplants, them into another "host" organism; this genetically engineered DNA becomes part of the host’s genetic makeup. Researchers have learned to use the tools of recombinant DNA technology (gene splicing) to do the same thing with substances other than tumor antigens (cytokines, for example). Not all immunotherapies using DNA are vaccines, technically speaking, but their goals are all the same--a steady supply of whatever substance is being used to stimulate the immune system.  

And not all treatments using DNA are immunotherapies. Other types of therapy using DNA treat cancer cells directly by replacing the damaged genes responsible for the cells’ abnormal growth, or by adding new genes that make the cancer cells more sensitive to anticancer drugs. For more information, please see the separate document "Gene Therapy." 

Other Active Specific Immunotherapies 

Lymphokine-Activated Killer (LAK) Cell Therapy: Scientists can produce large numbers of active, cancer-fighting T cells in the lab by treating a small number of T cells in a test tube with a cytokine (an immune system hormone) called interleukin-2 (IL-2). After being returned to a patient’s bloodstream, these special cells, called lymphokine-activated killer (LAK) cells, are more effective against cancer cells. Researchers are currently testing several ways to use these very active cancer-fighting cells.  

LAK cell therapy has shown promising results in animal studies, where it caused shrinkage of tumors in animals with lung, liver, and other cancers. While clinical trials in human patients have not yet produced results as successful as those in animals, researchers are constantly improving LAK cell techniques. They are testing these newly improved methods against melanoma, brain tumors, and other cancers. 

Tumor-Infiltrating Lymphocyte (TIL) Vaccine with Interleukin-2 (IL-2): Researchers examining tumors have discovered immune system cells deep inside the tumor tissue and have named these cells tumor-infiltrating lymphocytes (TILs). These cells can be removed from tumor samples taken from a patient and forced to reproduce in test tubes by treating them with IL-2. When injected back into the patient, these cells may be active cancer fighters.  

Success with TILs in laboratory animals has led researchers to try several different methods to increase the anti-tumor activity of TILs. Immunotherapies using TILs are being tested in clinical trials for people with melanoma, ovarian cancer, and other cancers. 

In a recent study, researchers from the National Cancer Institute (NCI) used a newer technique involving TILs in patients with advanced melanoma. After removing TILs from the body, the researchers treated the patients with chemotherapy to reduce the numbers of other white blood cells in the body. When the TILs were reintroduced, tumors shrank significantly in 6 out of 13 patients, and almost all of the patients have lived longer than expected. The results are very promising, although the technique is still experimental and larger studies are need.  

Source: American Cancer Society

Immunotherapy Frequently Asked Questions

Immunotherapy is a broad term for treatment that uses the body's immune system, either directly or indirectly to fight cancer. Immunotherapy is designed to repair, stimulate, or enhance the immune system's natural anti-cancer function through the use of substances known as biological response modifiers. Immunotherapy often lessens side effects that are caused by conventional cancer treatments.

What are biological response modifiers?

Biological response modifiers (BRM's) alter the interaction between the body's immune defenses and cancer, improving the body's ability to fight the disease. BRM's include hormones, antioxidant vitamins, cytokines and certain other natural drugs which may serve to recruit the cancer patient's immune system into more active participation. They prove to be most beneficial when used in combination with each other and/or with other treatments such as radiation and chemotherapy.

The effects produced by the agents used in immunotherapy may include:

•  enhancing a cancer patient's immune system to fight cancer cell growth;

•  eliminating, regulating or suppressing body responses that permit cancer growth;

•  making cancer cells more susceptible to destruction by the immune response;

• altering cancer cell's growth patterns to promote behavior like that of healthy cells;

•  enhancing a cancer patient's ability to repair normal cells damaged by other forms
   of cancer;

•  preventing a cancer cell from spreading to other sites in the body.

How does immunotherapy work?

The body has a natural ability to protect itself against diseases, including cancer. The immune system exists to fight foreign cells, including cancer, and when it is weakened by old age, environmental causes or other factors, it can be more easily overwhelmed by cancerous cells.

Immune system cells with several specialized functions must work as a team effort to successfully defend the body against cancer. Immune cells include both lymphocytes and monocytes and are found in the blood as well as in many other places in the body. Lymphocytes include B cells, T cells and NK cells.

B cells develop in bone marrow and produce antibodies. An antibody is a protein tailor-made to attach to a specific antigen. Foriegn cells exhibit one or more proteins not found on normal cells. Under the right conditions, antibodies may be constructed which latch onto the cancer specific antigens. working as tiny flags that alert immune cells to attach and destroy the foreign cells.

Different types of T cells have different immune functions: cytotoxic (killer) T cells directly destroy antigen marked cells; helper T cells activate the immune system and cytotoxic T cells; and suppressor T cells inhibit antibody production and other immune responses.

NK (natural killer) cells destroy cancer cells by producing powerful chemical substances known as cytokines that bind to and kill any foreign invaders. NK cells possess destructive ability that is substantially enhanced after exposure to some cytokines, especially interferons or interleukin-2. NK cells have shown the ability to eliminate metastatic tumor cells and thereby resist tumor spread. Using cytokines as a part of our BRM therapy in certain types of cancer, we have seen dramatic rises in natural killer cell count.

Monocytes are white blood cells that travel into tissues and develop, when needed, into macrophages as part of the immune response. Monocytes and macrophages play a key role in phagocytosis, a process by which some cells "eat" other cells and foreign invaders. The substances we use to enhance this natural process are called GM-CSF's "granulocyte macrophage colony stimulating factors).

Each individually tailored regimen of BRM's consists of the substances we believe to be best at boosting the immune system's response to the type cancer.

What benefits might I expect from immunotherapy?

In quality of life analyses of subjectively perceived problems in advanced cancer patients, the three worst problems are loss of physical strength, pain, and loss of stamina. Our experience has shown that BRM therapy helps many patients feel better, be more energetic and experience less depression.

Patients who are going to respond favorably to BRM therapy usually begin to notice the benefits quickly -- often within a week or two . We have also seen an improvement in extended survival in certain types of cancer using immunotherapy.

Will immunotherapy interfere with the effectiveness of my chemotherapy or radiation therapy?

To the contrary, immunotherapy actually complements these conventional forms of treatment while helping to lessen side effects commonly associated with them.

If immunotherapy works so well, why isn't everyone using it?

One reason is that researchers are used to dealing only in easil measured data, and subjective quality of life benefits are hard to precisely quantify. Conventional medicine can sometimes be slow to embrace new methods, but Steven Rosenberg, M.D., chief of surgery at the National Cancer Institute, is working to civilize the treatment of cancer, and his stratagem is immunotherapy. "Immunotherapy uses the body's own immune system, a system that evolved to detect exquisitely small changes in molecules to tell non-self from the body, to fight cancer. If we can take advantage of that system, we're more likely to have a treatment that is effective and carries minimal side effects," says Rosenberg.

Another reason is that because many of these natural supplements that we find so beneficial are unpatentable. This means that pharmaceutical companies do not want to go the major expense to fund a study for FDA approval when they will not be able to have a proprietary drug to bring in revenue to offset the cost of the study.

How can you tell if the BRM therapy is effective?

There are certain measurable markers, such as NK (natural killer) count and CEA (carcinoembryonic antigen) levels, which can be used to show the effects of BRM therapy. Natural killer cells have the ability to recognize and destroy certain tumor cels, so a rise in NK count is a positive indication that the immune system is probably working. CEA levels measure the amount of this particular antigen, which shows that there is a foreign substance under attack in the body. Along with the rise in natural killer count, there is often a corresponding fall in CEA levels in response to BRM therapy.

Source: Human Genome Project Information