Immunotherapy For Cancer

Tactics Tumors Use to Evade Immune Attack

Altering Their Characteristics

Under attack by the immune system, tumor cells generate variants lacking those features that mark them for destruction by T cells, other killer cells and antibodies. The process, called immunoselection, can lead to tumor cells that do not have tumor antigens 6r major histocompatibility antigens, which present tumor antigens to immune cells. Tumor cells can also lack co-stimulatory molecules, which activate T cells, and signaling molecules needed to respond to cytokines, such as gamma-interferon, that promote tumor cell killing by immune mechanisms.

Suppressing the Immune Response

Tumor cells can effect changes in the host that diminish or abrogate an effective immune response against them. Specific immunosuppression occurs when tumor cells deliver inappropriate or ineffective signals to T cells, reducing their number or ability to respond. Nonspecific immunosuppression is caused by other tumor cell products, such as TGF-beta, or by cancer drugs or irradiation.

Hiding from the Immune Response

Immune reactions are less effective or absent in several sites in the body, such as the brain, and so tumors there avoid immune attacks. Also, a dense tumor stroma consisting of connective tissues can shield tumor cells from immune recognition and destruction.

Exploiting the Immune System's Ignorance

Tumor cells may grow without eliciting any immune response. But an effective immune response can be generated by immunizing against tumor antigens-indicating that the potential for immune attack is not always activated.

Outpacing the Immune Response

Tumor cells can simply proliferate so quickly that the immune response is not fast enough to keep their growth in check.

Using Monoclonal Antibodies

For the past century scientists have hoped to enlist the extraordinary disease-fighting prowess of the immune system to destroy cancerous tumors, though most attempts proved futile. Today countless investigators are developing potent new biological therapies involving the immune response. One such therapy involves the use of monoclonal antibodies.

For immunotherapy to be successful, it must be able to distinguish cancer cells from normal cells. One way the immune system can recognize differences is by the different antigens expressed on the cell surface. If cancer cells displayed tumor–specific antigens on their surface, then perhaps a means could be devised to selectively target these cells for immune attack. Over the years human cancer cells have been injected into countless horses, sheep, rabbits, mice, and rats, and the antibodies collected and identified. The search for cancer antigens became easier when researchers discovered that antibody producing cells (i.e., plasma cells) could be made to survive definitely if they were fused with cancer cells. This enabled scientists to produce unlimited supplies of identical antibodies, or monoclonal antibodies, because any give antibody-producing cell produces only a single type of antibody. (Note: You can read about how monoclonal antibodies are produced in your textbook.)

Monoclonal antibodies have revealed a large array of antigens that exist on human cancer cells. Unfortunately, virtually all these antigens are also found on normal cells, which might therefore be damaged by antibody-based therapy. However, it may still be possible to use this therapy because the antigen in normal tissues may not be accessible to blood-borne antibodies, the cancer cells may express more antigen than normal cells do, and antibody-induced injury of normal cells may be reversible. Still, the fact that researchers have not been able to isolate cancer-specific antigens is disappointing.

Acting alone, antibodies bind to antigens on the surface of cancer cells. In doing so, they mark these cells for destruction by other immune components or cause them to self destruct. Antibodies can similarly target and attack the blood vessels feeding a tumor or the connective tissues (stroma) supporting it. And antibodies can neutralize or block the action of growth factors––chemicals that a tumor needs to grow. In addition, antibodies are used as guided missiles of sorts. They can deliver an array of damaging compounds (e.g., radioactive isotopes, chemotherapeutic drugs, toxins) to tumor sites.

Immunotherapy For Cancer: The Promise Of Vaccines

Over the years doctors have vaccinated many hundreds of cancer patients with malignant cells––either their own or those taken from another patient––usually irradiated to prevent further growth. Although occasional immune responses were observed, this vaccination strategy offered no way to monitor the vaccine’s effect on the immune system. In recent year researchers studying melanoma patients found evidence that a small proportion of patients did mount a specific immune response against their own tumor cells, and researchers are in the process of isolating the tumor antigens so that they might be tested in a vaccine. T cells do not “see” the whole protein antigen on the cancer cell, but only pieces of it. Investigators are now creating a list of potential tumor antigens, all of which are prime candidates for use as vaccine.

Among the most attractive targets for vaccines are abnormal proteins that are made when genetic mutations turn normal cells into-cancer-promoting cells. A long list of cancer-related genes––oncogenes and tumor suppressor genes––is now being compiled. And, of course, human cancers caused by viruses, such as cervical cancer, are prime targets for vaccine-based therapies.

Cancer vaccines are intended to induce T-cells or other components of the immune system to recognize and vigorously attack malignant tissue. While there have been some tumor regressions in early tests, there remains a great deal of work to be done to determine whether or not this therapy may prove effective in the future. Unfortunately such vaccines may injure normal cells to some degree.

New Cancer Treatments

Metastases are what kill the cancer patient. All too frequently, many small, undetectable metastases are already present by the time the patient’s cancer is first diagnosed. Presently, cancer treatment focuses on surgical removal and treatment with radiation and toxic chemicals (chemotherapy). Unfortunately, the treatments that kill cancer cells also affect normal cells, and there are often unpleasant side effects. Chemotherapy, for instance, has the greatest effect on rapidly dividing cells. This includes cancer cells, but also the cells lining the digestive tract and hair cells, which also divide frequently. Consequently, tumors treated with anticancer drugs may shrink, but most patients also have problems with nausea and diarrhea, and often lose their hair. And, unfortunately, cancer cells typically develop resistance to the drugs over time. If even just a few cells survive, they can proliferate and spread. Many of the new treatment strategies are being developed with the aim of preventing or treating metastases.

For metastasis to occur, some of the tumor cells must become invasive and cross the basement membrane to get to the lymphatic vessels or blood vessels. Studies of human cancers have shown that invasive cells produce higher than normal amounts of protein-digesting enzymes called metalloproteinases. Such enzymes may aid cell movement through the basement membrane by dissolving the proteins, particularly collagen, that make up this extracellular layer. The metalloproteinases are secreted in inactive form and must be converted to the active form. Some investigators think it may be possible to develop a drug that would block the activation of metalloproteinases, thereby suppressing invasion. That is not all there is to the metalloproteinases story, however. Normal tissues and tumor cells themselves also secrete a metalloproteinase inhibitor. Called TIMPs (for tissue inhibitor of metalloproteinases), these substances bind specifically to metalloproteinases and block their activity. The TIMPs, then, act as metastasis-suppressor proteins. Whether or not a cancer cell invades or metastasizes depends on the balance between the activator and inhibitory proteins. Someday, perhaps TIMPs, or drugs that mimic their activity, could be used to alter the balance and prevent invasion or metastasis.

Other potential metastasis inhibiting proteins have been discovered. One such protein, called nm23 (for nonmetastatic 23), is encoded by a gene that is missing or inactive in metastatic tumor cells. Studies of breast cancer patients have shown that patients whose tumor cells have high levels of nm23 have few metastases and a good prognosis, while those with low levels have many metastases and tend to die sooner. If the gene for nm23 could be turned on or replaced in tumor cells, it might be possible to suppress metastasis. Another approach is to use the levels of nm23 in tumors as an indicator for determining the most appropriate cancer treatment.

All of these possible treatments act by interfering with the metastatic process. But what about the patients who have many small secondary tumors at the time of diagnosis? Chemotherapy and radiation are useful in some cases, but the side effects are unpleasant at best, and life threatening at worst, and moreover the treatment may not help. What is needed are drugs that specifically arrest the growth of already established metastatic tumors without the severe toxic side effects of present chemotherapeutic agents. Clinical trials are beginning with a new group of synthetic compounds, called CAIs, which block the growth of certain types of secondary tumors. These agents are thought to interfere with the signaling pathways within the cell that causes the uncontrolled growth. The results of animal testing are promising, and investigators at the National Cancer Institute are eagerly awaiting the results of the first clinical trials in humans.

Developing new therapies is a long and difficult procedure, but researchers hope that by understanding the metastatic process new and more effective cancer treatments can be developed. Since one out of five people living today can expect to die of cancer, this work has important implications for all of us.

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