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    • 1 Cancer Immunotherapy
    • Abstract A tremendous amount of research is being done in an attempt to find a cure for the many types of cancer. This paper presents background information on cancer as well as the normal immune system response to cancer cells. The main focus of the paper is to characterize and introduce the two main goals of cancer immunotherapy: the attempts at making a cancer vaccine and the attempt to provide an in vivo immunological environment that is more conducive to the identification and destruction of cancerous cells. Both types of immunotherapy have been shown to cause the regression of cancer cells but no technique has been able to provide a clear cure for the disease. Recent advances and topics of importance to cancer immunotherapy are discussed in detail in an effort to explain how these techniques work in aiding the immune system and augmenting the anti-tumor immune response. Introduction According to the American Cancer Society, this year in the United States one in every four deaths will be caused by some form of cancer (Statistics, 04/02/00). Cancer presents a unique problem for the immune system because unlike an infection involving foreign cells, the problematic cells originate from within the organisms’ own body thus the cell has a similar composition as normal somatic cells. The immune system does have the means to identify and destroy cancerous cells, but often these cells are able to avoid identification by various mechanisms such as low Class I MHC expression or by inhibiting costimulatory signal production or expression (Goldsby et al., 1999). Costimulatory signals are just as important as MHC expression because antigen presentation cannot occur without them. A key focus in cancer immunotherapy is to
    • 3 elucidate the manner in which certain types of cancers are able to avoid or weaken identification by the cells of the immune system and to find a procedure that will aid in evoking an immune response capable of the destruction of the cancerous cells. Cancer Background Cancer cells are the result of a disruption of the cell renewal and death cycle, most likely as a result of a series of somatic DNA mutations (Goldsby et al., 1999). In general, the mutation results in a slowing or elimination of apoptosis while colony expansion increases. Once a cancer cell has formed, it often undergoes mitosis at a very high rate expanding into a colony of genetic clones. There are many types of cancers originating within different organs and systems. Some cancer causing mutations have been linked to genetic factors while others are linked to environmental factors such as certain chemicals from cigarette smoke and from UV light. Overview of the Immune Response to Cancer Cells If cancer cells do form in an organism, the immune system does have a variety of different ways that the unwanted cells can be eradicated. Research has shown that both the cell mediated and humoral immune response can play a role in the destruction of tumor cells (Goldsby et al., 1999). As part of the cell mediated response, T cytotoxic lymphocytes can recognize altered self-antigen as presented by class I MHC. Once self- antigen has been recognized, a T cytotoxic lymphocyte divides into effector cells known as cytotoxic T lymphocytes (CTLs) which can then destroy the cell that the antigen came from by cytotoxic activity (Goldsby et al., 1999). As mentioned earlier, some cancers can avoid being recognized in this manner by having a low expression of class I MHC or
    • 4 by removing co-stimulatory signals that are crucial to the presentation of antigen. In both cases, this limits the presentation and resulting recognition of self-antigen. Fortunately, another type of lymphocyte known as the natural killer cells (NK) specifically targets cells with low expression of class I MHC. The NKs can then destroy the cell by way of cytotoxic activity (Goldsby et al., 1999). NKs can also destroy tumor cells after being stimulated by the presence of antibodies that have recognized antigen on the surface of tumor cells. NKs have CD16 receptors on the cell membrane that bind to the Fc region of immunoglobulin. Immunoglobulin is secreted by B-lymphocytes as part of the humoral response. Immunoglobulins have antigen binding sites and an Fc region. The antigen-binding sites bind to antigen and the Fc region is what is recognized by a variety of cells such as NKs and Macrophages as well as other cells, which can then destroy the cell from which the antigen came. The Need for Immunotherapy Even though the immune response to cancer is very broad and very specialized it is obvious due to the high incidence of death of people with cancer that the immune system still has a difficult time copping with the disease. In an effort to increase the survivability for those with cancer, a large amount of research has been done and is continuing to be done with the hope of finding a cure. Immunotherapies of many varieties have been tested and are now used to aid the immune system in the identification of cancer cells and their subsequent destruction. Cancer immunotherapy can be divided into two categories: cancer vaccines and induction of immune response against specific antigens. The cancer vaccine focus has to do with stimulating immunity through the use of an outside source of antigens that are analogous with certain cancer
    • 5 cell antigens, while the immune response to specific antigens has to do with providing an environment that is conducive to the recognition, presentation, and the destruction of specific antigens and the tumor cells from which they came. Though no total cure for cancer has been discovered at this point, many immunotherapeutic techniques are being practiced that greatly increase the survival rates of cancer patients. Combinations of different techniques such as administering a vaccine as well as creating a more favorable immunological environment also have resulted in tumor regression. Cancer Vaccines One idea behind cancer vaccines is that by creating and injecting an antigen that is immunogenic and is at the same time identical to an antigen on or within tumor cells, an immune response will be created that will not only remove the injected antigen, but will also create enough antigen specific antibodies, B cells, and T cells that are capable of destroying the cancer cells. Often the source of antigen is the patient’s own cancer cells. Another focus behind cancer vaccines is the use of a recombinant virus that when introduced into cancer cells causes them to express antigens and various costimulitory signals. In both cases the idea is to create antigens that would elicit an immune response that would create memory B and T cells that would be specific for the antigens thus thwarting any future re-growth. Many different prototypes of cancer vaccines have been created. Some use the patient’s own cancer cells while others use recombinant viruses. Researchers from Hadassah University Hospital in Israel used irradiated mouse tumor cells as a source of antigen, as well as indomethacin injections which resulted in an anti-tumor response and protection from a normally deadly dose of murine mammary and lung carcinoma cells in syngeneic mice (Henderson., 2000). The investigators found that
    • 6 continuous injections of indomethacin throughout the immunization period as well as during the injection of the carcinoma cells was pivotal to the destruction of the cancer cells (Henderson, 2000). This demonstrates the usefulness of combining a cancer vaccine with an immune system stimulant. The researchers also found a correlation between the ability of indomethacin to stimulate destruction of the cancer cells and the level of endogenous prostaglandin within those cells. While anti-tumor immunity was expressed against murine lung and mammary carcinoma cells which posses high levels of endogenic prostaglandin, no immunity was shown for other murine tumor cells that contain low levels (Henderson, 2000). The mice which were injected with indomethacin remained healthy and displayed no signs of immune system dysfunction such as increased spleen size or excessive lymphoproliferation (Henderson, 2000). Dr. David Berd and his team at Thomas Jefferson University created another type of cancer vaccine (reviewed in Wynn, 1999). Similarly to the experiment discussed by Henderson, Berd’s experiment used the patients own cancer cells to create a vaccine. Berd used a patient’s own Melanoma cells but added a hapten to the cell instead of simply injecting irradiated cells. The hapten solves a common problem that often occurs when making a cancer vaccine, the problem of antigen tolerance (Wynn, 1999). Because a cancer cell originates within the organism it often has few molecules that appear as foreign and as mentioned earlier many cancer cells inhibit antigen presentation so it is never seen as a foreign or as a threat by the immune system cells. A hapten, which is antigenic but not immunogenic will be recognized as foreign and will initiate a small immune reaction. The hapten gets the identification process of the cancer cells going, hopefully after the cancer cell is processed, other antigens will be found on the cancer
    • 7 cell that will be recognized as altered-self antigen and will elicit an even more potent immune response capable of causing tumor regression. In the treatment phase, the patient's own tumor cells are taken and then the hapten is attached, the complex is then injected back into the patient also adding the Bacillus Calmette-Geurin adjuvant as well as a preliminary dose of cyclophosphamide (Wynn, 1999). In clinical studies, this type of vaccine treatment was able to increase survivability by more than fifty percent. This technique is being tested on and is showing promise for other types of cancer as well (Wynn, 1999). Another type cancer vaccine involves the use of recombinant viruses to serve as the vaccine. The virus is designed to target cancer cells and then infiltrate and code for the production of antigens, most commonly superantigens are chosen because of their ability to stimulate a large immune response. Construction of viruses that act as a vaccine for the treatment of murine tumors has been achieved (Carroll, et al., 1998). A research team in Oxford England created a recombinant virus that as well as coding for the antigen E. coli Beta-galactosidase, also coded for the cytokine interleukin-12 and the costimulatory B-7 molecule (Carroll et al., 1998). Interleukin-12 is a cytokine that has many functions in the immune response, it can induce the immune response from NK’s as well as being important in the transition of Tc lymphocytes to CTLs (Carroll et al., 1998). B-7 has a costimulatory effect and is found on most professional antigen presenting cells. The expression of B-7 is essential for the acceptance of antigen by a Tc lymphocyte (Carroll et al., 1998). After creating the virus, the virus was injected into mice that had been previously injected with murine colon carcinoma cells. Varying viruses were created, some coding only for antigen, some only coding for interleukin-12,
    • 8 some coding for B-7 only, and then viruses that coded for all three as well as a control group that received no virus injection (Carroll et al., 1998). Exogenous interleukin-12 also was given to some mice who also received the virus. The mice who received both the vaccine coding for the antigen and B-7 along with an exogenous supply of interleukin-12 showed greatest tumor nodule reduction and the greatest survival rate (Carroll et al., 1998). This is a case when the use of a vaccine as well as an immunolgic- inducing environment provided the best results in tumor regression. This experiment demonstrates the importance of the costimulatory molecules and immune system modulators in the destruction of cancer cells. Induction of Immune Response Another key focus in immunotherapy is the attempt to elicit an immune response by providing more favorable conditions for antigen recognition. This is being done in various ways from the provision of exogenous cytokines such as interleukin-12, interleukin-2, or by the growing of tumor antigen specific T lymphocytes in vitro, the use of other stimulating factors and by direct in vivo transfection of tumors with immunostimulatory genes. Studies have shown that adoptively transferred allogeneic antigen specific T cells are effective in the treatment of relapsed hematologic malignancies (Schultze et al., 1997). Efforts are being made to use T cells from the same individual to provide an even more potent immune response. The idea is to take naïve T cells and “educate” them for specific cancer antigen in vitro and then reintroduce them to the individual. Unfortunately, no real grasp of the benefits of therapy involving autologous antigen specific T cells has been discovered because no one has been capable of isolating and
    • 9 growing a large amount of antigen-presenting cells for the stimulation of the antigen specific T cells in vitro (Schultze et al., 1997). Antigen presenting cells are crucial to the development of antigen specificity in T cells, a process that occurs normally in the thymus. Attempts had been made using dendritic cells because they are the best antigen presenting cells, but little success had been found due to little proliferation and loss of antigen presenting effectiveness outside the body (Schultze et al., 1997). Scientists from the Dana-Farber Cancer Institute found that autologous B cells are able to act as an efficient provider for antigen as well as proliferate continually in vitro (Schultze et al., 1997). B cells, though not as potent of an antigen presenting cell as dendritic cells, were shown to proliferate and present antigen at a level high enough to allow for a large number of antigen-specific T cells to be formed (Schultze et al., 1997). This large number of antigen-specific T cells are then injected back into the patient with the hope of stimulating a greater degree of effectiveness for the destruction of tumor cells. The use of cyclophosphamide also has resulted in notable anti tumor activity in some types of tumor cells (Proietti et al., 1998). Italian researchers explain that the injection of this widely used chemotherapeutic agent, cyclophosphamide combined with the use of adoptive immunotherapy dramatically increased the regression of tumor cells (Proietti et al., 1998). Cyclophosphamide also has a bystander effect on T cytotoxic cells which helps to facilitate the recognition of cancer cells. Another approach defined by scientists at the National Jewish Medical and Research Center was to supply a gene that encoded for a superantigen, which should elicit a powerful immune response (Dow et al., 1998). The team used dogs with melanoma tumors and injected plasmid DNA that coded for the superantigen
    • 10 staphylococcal enterotoxin B to be produced inside the tumor and then expressed (Dow, Steven R., et all). Expression of the superantigen should evoke a very large immune response. This technique is similar to the use of the aforementioned virus vaccine method, but in this case the vector is injected locally. The overall response to the treatment was a regression of tumor size in 46% of the dogs, with the most regression seen in dogs with smaller tumors (Dow et al., 1998). The injected tumors showed increased numbers of both T cytotoxic and T helper cells as well as increased numbers of macrophages and increased levels of T cytotoxic lymphocytes were found in blood (Dow, et al., 1998) Dogs who received this treatment had a longer survival time as compared with those who only had a surgical excision of the cancer (Dow et al., 1998) A group of researchers from the University of California Los Angeles designed an experiment to elucidate the mechanism by which adoptive immunotherapy with tumor infiltrating lymphocytes (TILs) and interleukin-2 works in vivo (Economou et al., 1996). This therapy appears to provide dramatic shrinkage in metastic melanoma patients as well as renal cancer patients, however the mechanism by which this happens is unknown (Economou et al., 1996). In this experiment, nine patients, six with melanoma and three with renal cancer were injected with DNA marked TILs and also with marked non-tumor infiltrating lymphocytes. At certain intervals samples of tumor as well as other tissues were removed and analyzed but unfortunately the results did not show any difference between TILs and the non-TILs. (Economou et al., 1996). The experiment did provide insight into the life span of the different lymphocytes and the patterns of movement throughout the body (Economou et al., 1996). The hypothesis that the TILs are attracted
    • 11 specifically to tumor cells was left unsupported and the mechanism by which TILs reduce cancer cells was left unknown (Economou, James S. et al. 1996). Conclusion Even though the immune system does have mechanisms to identify and destroy cancerous cells, often these mechanisms fail or are not expressed in a manner that is strong enough to prevent the spread of the disease. Cancer is one example of how a system as broad and specialized as the mammalian immune system can be evaded. Different types of immunotherapeutic techniques have been tested and are now in use to aid the immune system in recognizing and destroying cancer cells. The search for a cancer vaccine and a variety of methods for manipulating the environment of the inner body to allow for better antigen recognition are two of the focuses of immunotherapy. Cancers exhibit many properties that make them very difficult to recognize as well as kill and the many diverse types of cancer makes one single unifying cure for cancer a very idealistic thought. In spite of its elusive nature, much has been learned about cancer and survival rates of those with the disease are increasing.
    • 12 Literature Cited 1) Carroll, Miles W., Willem W. Overwijk, Deborah R. Surman, Kangla Tsung, Bernard Moss, and Nicholas P. Restifo. “Construction and Characterization Of a Triple-Recombinant Vaccinia Virus Encoding B7-1, Interleukin12, and a Model Tumor Antigen” Journal of the National Cancer Institute. Vol. 90 Issue 24. 7p. December 16, 1998. Academic Search Elite. 2) Dow, Steven W., Robyn E. Elmslie, Andrew P. Willson, Lisa Roche, Cori Gorman, and Terry A. Potter. “In Vivo Tumor Transfection with Superantigen plus Cytokine Genes Induces Tumor Regression and Prolongs Survival in Dogs with Malignant Melanoma.” The Journal of Clinical Investigations. Vol.101 Number 11. 20p. June 11,1998. www.jci.org. 3) Economou, James S., Arie S. Belldegrun, John Glaspy, Eric M. Toloza, Robert Figlin, Jane Hobbs, Nancy Meldon, Randhir Kaboo, Cho-Lea Tso, Alexander Miller, Roy Lau, William McBride, and Robert C. Moon. “In Vivo Trafficking of Adoptively Transferred Interlukin-2 Expanded Tumor-infiltrating Lymphocytes and peripheral Blood Lymphocytes.” The Journal of Clinical Investigations. Vol. 97 Number 2. January 1996. www.jci.org. 4) Goldsby, Richard A., Thomas J. Kindt, and Barbara Osborne. Kuby Immunology. New York: W.H. Freeman Company, 1999. 5) Henderson, C.W. “Anti-tumor Immunity Induced by Indomethacin and Cancer Vaccine.” Cancer Weekly. March 21, 2000. P. 9. 2 P. Academic Search Elite. 6) Proietti, Enrico, Giampaolo Greco, Beatrice Gerrone, Sara Baccarini, Claudia Mauri, Massimo Venditti, Davide Carlei, and Filippo Belardelli. “Importance of Cyclophosphamide-induced Bystander Effect on T Cells for Successful Tumor Eradication in Response to Adoptive Immunotherapy in Mice.” The Journal of Clinical Investigation Vol. 101 Number 2. 24p. January 1998. www.jci.org. 7) Schultze, Joachman L., Sabine Michalak, Mark J. Seamon, Glenn Dranoff, Ken Jung, John Daley, Julio C. Delgado, John G. Gribben, and Lee M. Nadler. “CD40- activated Human B Cells: An Alternative Source of Highly Efficient Antigen Presenting Cells to Generate Autologous Antigen-specific T Cells for Adoptive Immunotherapy.” The Journal of Clinical Investigation Vol. 100. Number 11. 17p. December 1997. www.jci.org. 8) “Statistics” The American Cancer Society Homepage. April 2, 2000 http://www.cancer.org/statistics/index.html 9) Wynn, Paul. “Melanoma Vaccine Doubles Survival Rate, Nears Market.” Dermatology Times. Vol. 20 Issue 11, 3p. November 1999.