Immunotherapy, also called biotherapy or biological therapy, is a form of cancer treatment that utilizes the body’s immune system to fight off cancer. Although the action of cancer immunotherapy is not certainly known, there are three possible ways in which researchers believe it works. These include stopping or slowing the growth of cancer cells; stopping cancer from spreading to other body parts; and assisting the immune system to be more efficient in eradicating cancerous cells. The basis of cancer immunotherapy is boosting the body’s immune system to fight off cancer; sounds easy and logical in concept. Unfortunately, like most things in life, the actual scenario is far more complicated, and the pursuit of effective cancer immunotherapy has taken a relatively long time. However, immense progress has been made in the last decade.
The fundamental premise for cancer immunotherapy encompasses enhancement of the body’s immune system to fight off cancer. Traditional methods of treating cancer such as radiation, chemotherapy and surgery have obvious limitations. Surgery would not be effective in widespread or disseminated diseases, while chemotherapy causes adverse effects on normal cells in the process of killing cancer cells. Therefore, a treatment modality enhancing and utilizing the immune system to fight off or prevent cancer is an attractive and sound concept; hence, the fundamental premise of cancer immunotherapy. There is a common belief that the failure of the body’s “immune surveillance” is the key contributory cause of cancer. In addition, there is a lack of enough evidence that, in many cancer patients, the immune system slows down the spread and growth of tumors. This means that we require a competent immune system to prevent cancer from spreading once it has started. Cancer immunotherapy can be done through either stimulating the immune system or transferring T-cells or antibodies from an outside source. Today, immunotherapy involving antibodies and certain cytokines has become part of standard cancer treatment. Monoclonal antibodies and cytokines used in cancer immunotherapy are, however, not referred to as medication or drugs, but are labeled as Biological Immune Response Modulators, BIRMs (Charles, Travers, Walport, & Shlomchik, 2001). There are several types of cancer immunotherapy, including monoclonal antibodies, cancer vaccines, and non-specific immunotherapies.
Monoclonal antibodies are laboratory-made. They act like antibodies or part of the body’s immune system to fight off diseases. They are injected into the body, intravenously, and work by targeting protein molecules on the surface of cancer cells or antigens that support cancer cell growth. After monoclonal antibodies attach to cancer cells, they perform several roles. First, they may allow the immune system to destroy the cancer cell. Since the immune system does not always distinguish cancer cells, a monoclonal antibody can be directed to attach itself to certain parts of a cancer cell. This makes it easier for the body to find and destroy the cancer cell. Second, the monoclonal antibodies can prevent cancer cells from growing rapidly. Chemical compounds in the body referred to as growth factors attach themselves to cell surfaces and signal cell growth. Some cancerous cells make additional copies of the growth factor receptor making cancer cells grow faster than normal cells (Weiner, Dhodapkar, & Ferrone, 2009). Monoclonal antibodies block these receptors and prevent the growth signal from getting through cell membranes.
In addition, monoclonal antibodies can also deliver radiation directly to cancer cells. Without damaging healthy cells, monoclonal antibodies carry tiny radioactive particles directly to cancer cells. Researchers believe that these radioactive particles deliver low level radiation over a long duration. This forms a high-dose external radiation (radiation from a machine outside the body). Tositumomab (Bexxar) and Ibritumomab (Zevalin), for example, are used in the treatment of non-Hodgkin lymphoma. Monoclonal antibodies also can be used to diagnose cancer. Since they can carry radioactive particles with the use of special cameras, they can help to diagnose cancers such as prostate, ovarian and colorectal. Monoclonal antibodies are also used by pathologists to determine the type of cancer a patient might have had after his or her tissue is removed. Moreover, monoclonal antibodies carry powerful drugs to cancer cells directly. Once the monoclonal antibody attaches itself to a cancer cell, the cancer treatment drug that it is carrying enters the cancer cell and killsit without damaging other healthy cells. A good example is Gemtuzumab (Mylotarg), which used in the treatment of acute myeloid leukemia (AML).
Several therapeutic monoclonal antibodies are approved by the Food and Drug Administration (FDA) for human use. These include Alemtuzumab, Bevacizumab, Cetuximab, Gemtuzumab ozogamicin, Rituximab and Trastuzumab.
Alemtuzumab is an anti-CD52 monoclonal antibody used for the treatment of the most frequent form of leukemia in Western countries called Chronic Lymphocytic Leukemia, CLL (Colombo & Trinchieri, 2002). Upon binding to the CD52, Alemtuzumab starts a cytotoxic effect by antibody-dependent cell-mediated cytotoxicity mechanisms and complement fixation. Bevacizumab, a humanized monoclonal antibody, binds to and sterically interferes with vascular endothelial growth factor preventing the activation of receptors. Bevacizumab is mostly used in the treatment of colon cancer and renal cell carcinoma. It is known to increase the rate of response, interval of response, and duration of survival in a statistically relevant manner.
Cetuximab is a chimeric monoclonal antibody targeting extracellular domains of epidermal growth factor receptors (EGFR). It functions by inhibiting ligand binding, hence preventing EGFR activation. Mostly, it is indicated for the treatment of colorectal cancer. Other anti-EGFR monoclonal antibodies, still under development, include hR3, ABX-EGF and EMD 72000 (Gross, & Walden, 2008). However, none of these agents are currently beyond phase one of the clinical trials, although they hold substantial promise for the future.
Gemtuzumab ozogamicin is an anti-CD33 “immuno-conjugate” antibody that is chemically linked to a cytotoxic agent, calicheamicin. It is mostly administered in the treatment of acute myeloid leukemia (AML). When combined with intensive chemotherapy, trials have reported high complete responses (85 per cent) in young adults. Minimal side effects are associated with Gemtuzumab therapy.
Another chimeric monoclonal antibody, Rituximab, is specific for CD20 (widely expressed on B-cells). Researchers suggest that CD20 plays a role in calcium influx across plasma membranes, hence allowing for the activation of B cells. However, the actual function of CD20 and the exact mode of action of Rituximab is relatively unknown. Experiments with primates indicate that anti-CD20 treatment reduces peripheral B-cells by 98 percent, bone marrow B-cells and peripheral lymph node by up to 95 percent.
Approved by the FDA in 1998, Trastuzumab is a monoclonal antibody specific for the epidermal growth factor receptor 2 protein (HER2) (Yarden, 2001). It is clinically used in the treatment of breast cancer. Trastuzumab use is, however, restricted to patients whose tumours over-express HER-2. Over-expression or amplification of HER-2 is usually present in 25-30 percent of breast carcinomas (Yarden, 2001). It is associated with poor prognosis, aggressive tumour phenotype, reduced sensitivity to conventional chemotherapeutic agents, and non-responsiveness to hormonal therapy.
Non-specific immunotherapies also assist in the fight against cancer. Most non-specific immunotherapies are, however, administered at the same time or after other cancer treatments like radiation therapy or chemotherapy. Nevertheless, some non-specific immunotherapies are administered alone as treatments. Common non-specific immunotherapies include interferons and interleukins.
Interferons assist the immune system to fight cancer by slowing the growth of cancer cells. Interferons that are made in the lab called interferon alpha (Roferon- A [2a], Alferon N, Intron A [2b], are the most commonly used interferons in the treatment of cancer). Interferon alpha is mainly used in the treatment of non-Hodgkin lymphoma, kidney cancer, hairy cell leukemia, melanoma, kaposi’s sarcoma, and chronic myeloid leukemia (CML). However, interferon treatment is not devoid of side effects. These include an increased risk of infection, flu-like symptoms, thinning hair and rashes.
Interleukins help the immune system in producing cells that help in fighting cancer. Interleukin-2, IL-2, or Aldesleukin (Proleukin), an interleukin made in the laboratory, is used to treat skin cancer and kidney cancer (Trinchieri, 2003). Side effects of IL-2 include low blood pressure and weight gain, which can be treated with other medications.
Vaccines assist the body to fight off cancer. Cancer vaccines are of two types: treatment vaccines and prevention vaccines. Treatment vaccines may stop the growth of cancer cells, prevent cancer from reoccurring, or destroy any remaining cancerous cells after administration of other modes of treatment. Cancer vaccines are designed to be specific. This means that they are supposed to target cancerous cells and not healthy body cells. However, Sipuleucel-T (Provenge) is used in the treatment of metastatic prostate cancer and is the single treatment vaccine permitted in the United States today (Garcia-Lora, Algarra, Collado, & Garrido, 2003). Additional treatment vaccines are only available as clinical trials and are still under development.
Prevention vaccines are administers to an individual with no cancer symptoms to prevent the development of cancer (or other diseases). For example, Gardasil vaccine prevents a woman infection with Human Papilloma Virus (HPV), a virus that causes cervical cancer (Rosenberg, Yang, & Restifo, 2004). Gardasil is the first FDA-approved cancer vaccine. Cervarix vaccine is also an approved vaccine used in the prevention of cervical cancer in women and girls between 10 and 25 years (Rosenberg, Yang, & Restifo, 2004).
Today, several advances have been made in immunotherapy. Testing and development of second generation immunotherapies are already underway. Although antibodies targeted at disease causing antigens can be effective under certain circumstances, their efficacy is usually limited by other in many cases. For cancerous tumors, the microenvironment is immunosuppressive. It allows the tumors that exhibit unusual antigens to flourish and survive despite the immune response generated by the patient. Cytokines such as Interleukin-2 play a fundamental role in modulating the immune response. They are used in conjunction with antibodies to generate a more devastating immune response against cancer. Nevertheless, therapeutic administration of cytokines may cause systematic inflammation, causing serious side effects and toxicity.
Some natural products have also shown promise in stimulating the immune system to fight off cancer. Research shows that mushrooms like Agaricus blazei and Reishi are able to stimulate the immune system. Agaricus blazei is a potent stimulator of natural killer cells and is rich in beta-glucans and proteoglucans, which are effective stimulators of macrophages (Ribas, Butterfield, Glaspy, & Economou, 2003). Isolated and highly purified compounds from medicinal mushrooms, for example, Polysaccharide-K (isolated from Trametes versicolor) and lentinan (isolated from Shiitake), have been adopted into the health care system of some countries, such as Japan (Ribas, Butterfield, Glaspy, & Economou, 2003). In the 1980s, Japan approved the use of Polysaccharide-K on patients undergoing chemotherapy to stimulate the immune system. A mixture of a number of mycological extracts including Polysaccharide-K and lentinan is also sold commercially in Australia as MC-S.
Does immunotherapy have any weaknesses or problems? The main likely problem with cancer immunotherapy is the need for time for the body to respond. This is because in some patients, for example, those with Burkitt’s lymphoma, time is what the patient does not have (Copier, Whelan, & Dalgleish, 2006). Cancer immunotherapy also does not work in cases of large tumors, and the tumor needs to be reduced in size (debulked) before immunotherapy has a chance to work. Immunotherapy is also immensely costly, and its price is not likely to drop any time in the near future. Monoclonal antibodies are also fabulously expensive. Personalized vaccines do not come cheap either.
For the patient, there are several basic questions that one should ask the doctor when he or she checks for immunotherapy. Why does the doctor recommend immunotherapy? What are the goals of the treatment? Will immunotherapy be your only treatment? If not, what other treatments will form part of your treatment plan? How will you receive immunotherapy and how often? What are the possible long term and short term side effects? How will the treatment affect your daily life? Will you be able to perform your usual activities, work and exercises? What clinical trials of immunotherapies are open for you?
In conclusion, many forms of cancer immunotherapy such as monoclonal antibodies save and prolong many lives making it, today, an established treatment modality. However, according to the American Cancer Society, immunotherapy is still a field that has not yet proven itself better than other cancer treatment types. Nevertheless, it is a field that researchers believe hold a lot of promise for the future. Several other advances in the treatment of cancer will probably come from this field. Times Magazine interestingly voted in two cancer researchers, Dr. Doug Schwartzentruber and Dr. Larry Kwak, for its list of world’s top100 most influential people in 2010. Both researchers are in the forefront of cancer vaccine research. In spite of the high profile failures of immunotherapeutic treatments, in oncology, benefits for patients with a range of cancerous tumors have been relied. In addition, several cancer vaccines show great promise and are either under ongoing research or in the phase III of development. Although many hurdles still remain in the cure or prevention of cancer by using immunotherapy, there is at least some light at the end of the tunnel.