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C2 Paper #124 Disclaimer—This paper partially fulfills a writing requirement for first year (freshman) engineering students at the University of Pittsburgh Swanson School of Engineering. This paper is a student, not a professional, paper. This paper is based on publicly available information and may not provide complete analyses of all relevant data. If this paper is used for any purpose other than these authors’ partial fulfillment of a writing requirement for first year (freshman) engineering students at the University of Pittsburgh Swanson School of Engineering, the user does so at his or her own risk. THE POTENTIAL OF IMMUNOTHERAPY FACILITATED BY GENE THERAPY FOR TREATMENT OF PROSTATE CANCER Sagar Kumar, [email protected], Budny 10:00, Katie Banbury, [email protected], Budny 10:00 Abstract—Since the late 1800’s, gene therapy, the transplantation of normal genes into cells in place of missing or defective genes to correct genetic disorders, has promised innovation in many areas, ranging from agriculture to medicine. Current and future applications of gene therapy are extensive, but this paper will specifically focus on the combination of gene therapy with immunotherapy the prevention or treatment of disease by stimulating the immune system and the potential of these combined therapies to treat cancer. The recent discovery of this groundbreaking combination makes it possible to strengthen the immune system and program it to destroy cancerous cells. We will discuss in detail the history of gene therapy, how gene therapy methods are altered in immunotherapy, and why this approach shows such great potential in cancer treatment, specifically the treatment of prostate cancer. Recently, the first successful immunotherapy vaccine, Sipuleucel-T, was approved by the United States Food and Drug Administration (FDA). That prostate cancer is the most common and the second most deadly cancer in men makes this breakthrough even more significant. We will delve into possible future directions of immunotherapy for cancer treatment, investigating the use and sustainability of the Sipuleucel-T vaccine in conjunction with conventional cancer treatments, such as chemotherapy and radiation, through the analysis of current and concluded clinical trials. Key Words—Gene Therapy, Immunotherapy, Prostate Cancer, Sipuleucel-T, Conventional Cancer Therapy, Immunotherapy, Immune System HISTORY AND DEVELOPMENT OF CANCER VACCINES Cancer vaccines, also known as biological response modifiers, work by stimulating or restoring the immune system’s ability to fight infectious cancer cells. The immune system is a complex network of cells, tissues, organs, and the substances they make that allow the body to fight infections and other diseases. The immune system defends the body from disease-causing microbes and can protect the body against threats posed by certain damaged, diseased, or abnormal cells, University of Pittsburgh Swanson School of Engineering 1 Submission Date 2017-02-10 including metastatic cancer cells. White blood cells, leukocytes, play the main role in immune responses. They protect the body against diseases that causes microbes and abnormal cells. Other types of leukocytes, known as lymphocytes, provide targeted protection against specific threats. The major groups of lymphocytes responsible for carrying out immune responses against threats are B cells and T cells. B cells make antibodies, which are large proteins that bind to foreign invaders and abnormal cells to destroy them. On the other hand, T cells can either prompt infected and abnormal cells to self-destruct, inducing a process called apoptosis, or they can kill infected and abnormal cells by releasing toxic chemicals. Contrary to typical abnormal cells, cancer cells carry antigens, a toxin or other foreign substance that induces an immune response in the body, which mark healthy cells with an immune trigger. In response, the immune system mounts an attack on the healthy cell because of the presence of an infectious foreign substance, leaving the original cancer cell unharmed. Several factors make it difficult for the immune system to target growing cancers, including the difficulty of the immune system to recognize the cancer cells due to the very slight alteration in the cell surface proteins from a healthy cell. For this reason, cancer vaccines were created [1]. There are two broad types of cancer vaccines: preventive and treatment. Preventive vaccines are intended to prevent cancer from developing in healthy people, where treatment vaccines are meant to treat an existing cancer by strengthening the body’s natural immune response. Human papillomavirus and hepatitis B virus vaccines are examples of treatment vaccines. Cancer treatment vaccines are still being developed and researched, however, there is currently one approved cancer treatment vaccine, Sipuleucel-T, for the treatment of metastatic prostate cancer. Cancer vaccines, regardless of their type, employ modified antigens to help the immune system recognize and fight infectious cells. These vaccines work by stimulating the production of antibodies that bind to specific targeted tumor cells and block their ability to cause infection. All cancer preventive vaccines approved by the FDA have been made using antigens from microbes, which are bacteria that cause or contribute to the development of cancer. Throughout this paper, the sustainability of SipuleucelT will be discussed in detail. For this discussion, sustainability Sagar Kumar Katie Banbury will be defined as both increasing the “quality of life” and the extent to which Sipeuleucel-T will be significant in the future. Cancer treatment vaccines are also being developed using weakened or dead cancer cells that carry cancer associated antigen(s) or immune cells that are modified to present such antigens on their surfaces. These cells can come from the patient themselves, resulting in an autologous vaccine, or the cells can come from another patient, resulting in an allogeneic vaccine. Regardless of the various development methods, cancer vaccines delay the growth of cancer cells and, in some cases, eliminate it completely [1]. First Gene Therapy Adenosine Deaminase (ADA) deficiency, a condition that leaves patients substantially more susceptible to contracting infections and diseases, was incurable until September of 1990 when Dr. W. French Anderson conducted the very first gene therapy trial on a four–year old girl at the NIH Clinical Center. The therapy consisted of Dr. Anderson inserting genes that boosted the production of ADA into his patient’s previously extracted white blood cells. After the white blood cells were injected with ADA boosting genes, the white blood cells were then inserted back into the four-year old girl. This process, however, was not designed on a whim. The development of this treatment began in 1985, when doctors Kenneth Culver, W. French Anderson, and Michael Blaese found that cells from patients with ADA deficiency could be corrected in tissue culture, meaning that the cells were grown in a lab. The doctors used a retrovirus, an RNA group which hosts tumor specific enzymes, to deliver the corrected ADA genes into the ADA deficient cells, thereby boosting the production of ADA. In 1986, the team of doctors studied the transfer of corrected genes into the bone marrow of animals. From this study, they discovered that there was an insufficient number of cells receiving the corrected gene. Through extensive research, in 1988 the group of doctors found that transferring the genes into white blood cells instead of the bone marrow greatly increased the number of cells that accepted the corrected gene. The success and phenomenal results of this new delivery system prompted the group of doctors to consider the administration of the treatment in humans. Finally, in 1990 the team worked with Dr. Steven Rosenberg to test the safety and effectiveness of the gene therapy on humans. After the gene therapy was studied and approved, the team of doctors decided to conduct the gene therapy on a four-year old girl who had ADA deficiency. The development of this gene therapy has led researchers around the world to develop different gene therapies by stimulating the immune system to treat various diseases. Figure 1 below summarizes the process of gene therapy [2]. Figure 1- Description of the step-by-step process of gene therapy First Immunotherapy Immunotherapy, the prevention or treatment of disease with substances that stimulate immune system response, is a branch of gene therapy used in the treatment of cancer. The use of immunotherapy began in 1796 when doctor Edward Jenner designed a vaccine with cowpox to counteract the effects of smallpox. Using the design of this vaccine, doctor Steven Rosenburg developed a vaccine which would be useful in the treatment of metastatic cancers, such as prostate cancer. In 1987, cytotoxic T-lymphocyte antigen 4 (CTLA-4) was discovered, which researchers then studied to find that CTLA4 prevents T cells, cells deployed by the immune system when foreign invaders are recognized, from attacking tumor cells. This discovery led researchers to question whether blocking CTLA-4 would allow the immune system’s T cells to successfully attack foreign tumor cells. Through extensive research, researchers found that by using antibodies to block CTLA-4’s interaction with T cells, the addition of antibodies would allow the immune system’s T cells to attack and eradicate the tumor cells in mice. As more research was conducted, Bristol-Myers Squibb, a pharmaceutical company which was a part of a biotechnology firm called Medarex, acquired the rights to the antibody that successfully blocked the CTLA-4. Bristol-Myers Squibb then used the antibody on patients who had been suffering from metastatic melanoma and found that the patients who used the antibody lived an average of 10 months longer than the patients who had refused the antibody treatment. This immunotherapy treatment was the first treatment that had extended life in an advanced melanoma trial. Moreover, a biologist in the early 1990’s discovered a molecule that was expressed in dying T cells, which he named programmed death 1 (PD-1), which was revealed to best another T cell disabler. After this observation, an antibody was designed that would target and destroy PD-1. This antibody produced remission in multiple patients regardless of their cancer type. After this antibody was used as treatment, 2 Sagar Kumar Katie Banbury clinicians reported that across 300 cancer patients, tumors shrunk in 31% of melanoma patients, 29% of kidney cancer patients, and 17% of lung cancer patients, making this antibody extremely successful and revolutionary for its time. Although both anti CTLA-4 and anti PD-1 antibodies were very successful, some patients experienced tumor growth which was then followed by complete remission months later, showing that neither antibody produced immediate results. Anti CTLA-4 antibody and anti PD-1 antibody are currently the most effective forms of cellular immunotherapy. Both antibodies restrict the immune system from attacking the cells, T cells. The results of the first successful immunotherapy have led scientists to further study immunotherapy and design various cellular immunotherapies for various diseases and cancers [3]. Oncolytic Virus Therapies Oncolytic virus therapy works differently than the other therapies in that this therapy uses a modified virus that causes tumor cells to self-destruct, which generates a stronger immune response against the cancer. An example of oncolytic virus therapy is ProsAtak, which uses a disabled virus as a vector to deliver a gene directly to tumor cells, and is followed by an anti-herpes drug called Valtrex, which kills the cancer cells containing the gene that was originally delivered by the disabled virus [4]. ProsAtak will be described later to show its effectiveness in the treatment of metastatic prostate cancer. Checkpoint Inhibitors Another promising approach to the treatment of cancer using immunotherapy is through the use of checkpoint inhibitors. This type of treatment works by targeting molecules that serve as checks and balances in the regulation of immune responses. Checkpoint inhibition therapy works in two ways, either by blocking inhibitory molecules or by activating stimulatory molecules, which both are very effective in getting the immune system to fight against the cancer cells, which are often not recognized by the immune system since the cancer cells contain antibodies that the immune system views as healthy. These treatments are designed to enhance anticancer immune responses that already exist in the patient’s body, and if the anticancer immune response is not present in the patient’s immune system, these treatments create the anticancer immune response [4]. This treatment however, is very new and not much research has been conducted. However, based on the current experimental results, this branch of immunotherapy shows great potential in increasing the immune response in metastatic cancer patients, which could potentially eradicate cancer cells from a patient’s body. IMMUNOTHERAPY: THE SEVEN BRANCHES Immunotherapy is used in the treatment of diseases, more common in the treatment of cancer, using substances that stimulate the immune response within the patient. Since immunotherapy is a relatively new type of cancer therapy, the potential of such treatment is large. Currently, there are seven broad categories of immunotherapy: therapeutic vaccines, oncolytic virus therapies, checkpoint inhibitors, adoptive cell therapies, adjuvant immunotherapies, cytokines, and monoclonal antibodies. All of these categories hold great potential in the treatment of metastatic cancers even though they all work differently [4]. In terms of sustainability, all seven branches of immunotherapy play a role in improving the “quality of life” in cancer patients who opt to use the therapies. All branches improve the conditions of cancer patients and help them deal with upcoming debilitating conditions, which further supports the claim that immunotherapy improves the patient’s quality of life. Adoptive Cell Therapies Therapeutic Vaccines Adoptive cell therapy is a unique branch of immunotherapy in that the treatment is ex vivo, meaning the treatment does not actually take place within the body of the patient. In this therapy, immune cells are extracted from the patient and then genetically modified and treated with chemicals to enhance their activity and response strength in the patient’s body. Once the immune cells have been genetically modified, the cells are then injected back into the patient to improve the immune system’s anti-cancer response [4]. Therapeutic vaccines are designed to provoke an immune response against antigens that are specific to the tumor as well as antigens that are in general association with the tumor. These vaccines work by telling the immune system to attack the cancer cells that have these antigens on their outer membrane. Provenge, a therapeutic vaccine for prostate cancer, has been approved by the FDA after a phase III trial indicated that the vaccines increased the rate of survival in metastatic prostate cancer patients by more than four months [4]. Although Provenge will be further explained later, it should be noted that this therapeutic cancer vaccine has very few side effects and the effectiveness is unmatched when compared to other courses of treatment. Monoclonal Antibodies An often-underestimated immunotherapy treatment using monoclonal antibodies is a very successful and effective course of treatment in metastatic cancers. Monoclonal antibodies are molecules that are generated in a lab, and the job of these antibodies is to target specific antigens on tumors. Unlike polyclonal antibodies which require the secretion a 3 Sagar Kumar Katie Banbury network of multiple B cells to target a single antigen, monoclonal antibodies are more efficient because they only require the secretion of one B cell [4]. This treatment, like all immunotherapy treatments, is designed to generate an immune response that provokes the immune system to target tumor associated antigens which in result could potentially eradicate any cancer cells present in the patient’s body. Although most prostate cancer patients have adenocarcinomas, there are other types of prostate cancer: sarcomas, small cell carcinomas, neuroendocrine tumors, and transitional cell carcinomas. All of these types of prostate cancer have been shown to be treated through the application of the different branches of immunotherapy mentioned above. Figure 2, above, shows where the immunotherapy is applied [4]. Regarding sustainability, defined here as “quality of life”, the application of immunotherapy in prostate cancer patients has clear implications to human quality of life. Because immunotherapy enables doctors to manipulate the cancer patient’s immune response, this therapy enhances the ability of investigators to find the underlying cause of the weak immune response which can be fixed and strengthened with the use of immunotherapy. This therapy has great potential to increase the quality of life by expediting the search for treatments and cures for prostate cancer. Adjuvant Immunotherapies and Cytokines Cytokines and adjuvant immunotherapies are not individual treatments on their own; they are two branches of immunotherapy that are used in combination with the other branches of immunotherapy. Cytokines are messenger molecules that help control the growth and activity of immune system cells [4]. Using cytokines alongside the other immunotherapies is beneficial because each immunotherapy is dependent on the activity of immune cells. Adjuvant immunotherapy utilizes adjuvants, which are substances that boost the immune response. Based on the descriptions of the other branches of immunotherapy, adjuvants can be used in every immunotherapy so that the immune response in increased which in result would cause the other therapies to work more efficiently and increase their potential in eradicating the body of metastatic cancer cells. Although all seven branches of immunotherapy are broad, their potential in curing cancer is phenomenal and crucial if positive long term results are desired at the risk of a few mild side effects. Therapeutic Vaccines In a phase III trial of PROSTVAC conducted by Bavarian Nordic Inc., a therapeutic cancer vaccine consisting of virus’s vaccinia and fowlpox to deliver prostate-specific antigens (PSA) directly to prostate cancer cells, the immunotherapy showed tremendous results. The vector was shown to stimulate an immune response against PSA, which led the immune system to attack the cancer cells in the prostate of the patient. The results of this trial were promising and on average led to an 8.5-month increase in the life expectancy of metastatic prostate cancer patients [5]. The results of therapeutic cancer vaccine trials show that it is the most effective form of immunotherapy in the treatment of prostate cancer. APPLICATIONS OF THE SEVEN BRANCHES OF IMMUNOTHERAPY Figure 2- Shows location of tumor in prostate Oncolytic Virus Therapies Oncolytic virus therapy has also shown promise in the treatment of prostate cancer. ProsAtak, an effective oncolytic virus therapy, uses a disabled virus as a vector to deliver a gene directly to the tumor cells in the prostate. After the vector has delivered the gene, the patient is given an oral anti-herpes drug, Valtrex, to kill the cancer cells containing the gene. This therapy is currently being used in combination with radiation therapy. A phase II/III trial conducted by Advantagene Inc. showed that the use of oncolytic virus therapy, ProsAtak, with radiation therapy greatly reduces the side effects of the radiation, which also strengthens the significance of the therapy in terms of sustainability, therapy and increases the rate at which cancer cells are killed. The results also showed that the rate of recurrent cancer cells decreased significantly, making oncolytic virus therapy very effective in the treatment of metastatic prostate cancer [6]. As mentioned earlier, the potential of immunotherapy is enormous. More specifically, prostate cancer is an example of a cancer that has the potential of being completely resolved using immunotherapy. In prostate cancer, cells in the prostate gland begin to grow uncontrollably. The majority of prostate cancers are adenocarcinomas that root from the gland cells, which make the prostate fluid that is added to the semen. Checkpoint Inhibitors Nivolumab, a checkpoint inhibitor used in a phase II trial conducted by Sidney Kimmel Comprehensive Cancer Center, 4 Sagar Kumar Katie Banbury shows results that checkpoint inhibition therapy is successful in the treatment of prostate cancer. The results of the study showed that Nivolumab blocked the biomarkers on proteins that help tumor cells escape the surveillance of the immune system, and in response to the blocking off biomarkers, the immune system was able to target and destroy the tumor cells in the patient’s prostate [7]. Therapeutic application checkpoint inhibitors are currently still being studied, but based on the published results, these inhibitors can often prompt the remission of prostate cancer. The potential of checkpoint inhibitors will increase as more research and experiments are conducted. Adjuvant Immunotherapies and Cytokines Adjuvant immunotherapy and the use of cytokines are complementary treatments. Basically, the two treatments are utilized to enhance the effectiveness of other immunotherapy treatments. Both treatments are used to boost the effectiveness of Sipuleucel-T, a therapeutic cancer vaccine developed to treat metastatic prostate cancer. Using adjuvant immunotherapy along with Sipuleucel-T in a phase II study conducted by the Masonic Cancer Center at the University of Minnesota, researchers found that the speed at which the Sipuleucel-T vaccine stimulated the patient’s immune response had nearly doubled as opposed to when patients were treated with just Sipuleucel-T [10]. These results had indicated that the application of adjuvant immunotherapy was significant in the effectiveness of the therapeutic cancer vaccine. Cytokines work by controlling the growth and activity of immune system cells, similar to adjuvant immunotherapy. A phase II trial using CYT107, a cytokine used to stimulate the immune system, conducted by Fred Hutchinson Cancer Research Center showed that the application of cytokines, after the application of Sipuleucel-T, greatly reduced the ability of the tumor cells to spread to other areas of the prostate once the tumor cells had started reacting to the immune system attack (VII). This study proved that the application of cytokines does indeed boost the effectiveness of other immunotherapy treatments such as the therapeutic cancer vaccine SipuleucelT. Adoptive Cell Therapies Another successful application of immunotherapy has been through the branch of adoptive cell therapy, where immune cells are removed from a patient, genetically modified to enhance immune response, and then re-introduced into the patient to improve the immune system’s anticancer response. A phase II trial, conducted by Jonsson Comprehensive Cancer Center, used genetically modified T cells to target cancerspecific antigen NY-ESO-1, a protein present on tumor cells. The adoptive cell therapy successfully targets and kills the cancerous antigen and allows the immune system to kill the cancer cells [8]. The application of adoptive cell therapy has the potential to rid a patient of the metastatic cancer cells present in his prostate. Monoclonal Antibodies SIPULEUCEL-T, A THERAPEUTIC IMMUNOTHERAPY VACCINE The application of monoclonal antibodies in the treatment of prostate cancer has been just like the application of therapeutic cancer vaccines. Monoclonal antibodies are generated in a lab and used to stimulate an immune response in cancer patients. Results from a phase I/II trial of Tisotumab Vedotin, an engineered monoclonal antibody, conducted by Genmab indicated that monoclonal antibodies truly play a big part in the remission of prostate cancer. The engineered antibody targets a protein involved in tumor signaling, and prompts the immune system to respond to the protein as a foreign substance. After the immune system, has identified the infectious protein, an immune response is triggered and the immune system is directed to kill the protein [9]. Since tumor cells cannot function without the presence of its proteins, this therapy causes the tumor cells to die overtime which in response eliminates the tumor cells from the patient’s prostate. Because monoclonal antibody treatment is a relatively new therapy, there are multiple research studies and experiments being conducted to find the extent of how effective the therapy really is. As of now, the results found by Genmab show that the use of monoclonal antibodies have the potential to eradicate metastatic cancer cells. Sipuleucel-T, also known as PROVENGE, is an autologous cellular immunotherapy vaccine designed to stimulate a patient’s immune system against cancer. Sipuleucel-T is currently the only therapeutic cancer vaccine that has been approved by the FDA and is now being used to treat metastatic prostate cancer. Figure 3 below clearly shows the step-by-step process of the vaccine [11] [13]. There are several steps in the administration of SipuleucelT. First, the patient’s blood is run through a machine in a process called leukapheresis. During this process, the patient’s immune cells are collected. Then, these immune cells are exposed to a protein which is intended to stimulate and direct them against prostate cancer. After the immune cells, have been exposed to the protein, the activated cells are then returned to the patient to treat the prostate cancer. SipuleucelT is administered through IV in a cycle of three doses, over two week intervals [11]. This cancer vaccine is composed of autologous presenting cells (APCs), also known as” accessory cells”, which display antigens on their surface. The APCs are activated by the recombinant human protein, PAP-GM-CSF, consisting of prostatic acid phosphatase (PAP), which is an antigen expressed in prostate cancer tissue, linked to granulocyte- 5 Sagar Kumar Katie Banbury macrophage colony-stimulating factor (GM-CSF), an immune cell activator [11]. In addition to APCs, Sipuleucel-T contains numerous T cells and B cells which aid in the remission of metastatic prostate cancer cells. The application of SipuleucelT has on average increased the life expectancy of metastatic prostate cancer patients by three years, proving that it is a crucial therapy in the treatment of prostate cancer. With respective to sustainability, the application of the cancer vaccine Sipuleucel-T to metastatic prostate cancer patients has the potential to drastically improve the quality of life of individuals with this debilitating disease and to prevent future persons from developing this disease. In addition, gene therapy with Sipuleucel-T may be applied to many other metastatic cancers and improve the quality of life of individuals with these diseases by treatment and increase overall quality of life by preventing more individuals from developing these diseases. Not only does this vaccine improve the quality of life, it also shows how significant this treatment will be in the future. The contents of this vaccine have the ability to be passed down to offspring which in response would cause an improved immune response which could help people fight diseases without the use of various therapies. This effect supports the claim that in terms of sustainability, Sipuleucel-T has great significance towards the treatment of cancer in the future and in general has great significance towards the enhancement of the quality of life. chemotherapy, the foundation of treatment of metastatic disease, damages healthy cells, causing fatigue, pain, nerve damage and other debilitating symptoms. There has been extensive research and success in animal models with the combination of immunotherapy -- which boosts the body’s natural defenses to fight the cancer -- and these conventional therapies in animal models, setting the stage for clinical trials using this treatment strategy. Immunotherapy presents the possibility of cancer treatment with far fewer detrimental effects [12]. Using immunotherapy towards the treatment of cancer, as mentioned above, holds great value when talking about sustainability. Not only does the application of immunotherapy hold great significance in the treatment of cancer in the future, but in the short term, immunotherapy has shown to increase the quality of life in cancer patients. Preliminary evidence from preclinical and early phase clinical trials indicates promising results when conventional anticancer therapies are used in combination with immunotherapy. Recently, phase III clinical trials of multiple vaccines provided evidence that immunotherapies can prolong survival in patients with metastatic cancer, providing a therapy that harnesses the immune system to provide robust and adaptable cancer treatment rather than a rigid and destructive one. However, therapeutic cancer vaccine treatment alone is not sufficient; it is necessary to combine these cancer vaccines with conventional cancer treatment for optimal results [14]. Practical Application of Immunotherapy with Conventional Cancer Treatment Despite the emergence of new and improved therapies over the past few years, the goals of reducing the risk of disease and improving the quality of life are not always reached. Although the conventional treatments are life extending, they are rarely curative. However, the addition of immunotherapy to standard treatments, through the use of therapeutic cancer vaccines, has proven to complement traditional cancer therapies by inducing a therapeutic antitumor immune response [14] [15]. Figure 4 briefly shows the mechanisms involved in the application of conventional cancer treatments. Figure 3 - Shows how the vaccine works in a few steps IMMUNOTHERAPY FOR CANCER TREATMENT For many years, the conventional cancer treatments have been chemotherapy and radiation. Although they are somewhat successful, these treatments are harsh on the patient's body and have myriad side effects. For example, 6 Sagar Kumar Katie Banbury immunomodulatory effects of radiation and radiation’s effect on tissues. A great deal of preclinical research into combining radiation therapy with active therapeutic cancer vaccines has been shown in clinical studies using this combination as a multimodal therapy for cancer [14] [15]. FUTURE DIRECTIONS The immune system is flawed in that it normally does not recognize and kill cancer cells because it deems their surface proteins as “normal.” As a result, to be able to gain control of the immune system, therapeutic cancer vaccines are extremely promising treatments. So far, the clinical impact of vaccination alone has been limited. However, suppressed immunogenic cells that are a result of the vaccine could potentially be cleared or inhibited with the combination of vaccine therapy and conventional cancer treatment such as chemotherapy and radiation therapy. This potential is large because cancer cells treated conventionally become more vulnerable to T cells, which can increase the effectiveness of the vaccination when combined with standard cancer treatments. Since each of the different treatments has unique features that can enhance the success of cancer vaccines, a multimodal approach, including several therapy platforms in combination with the vaccines, could possibly result in even greater collaborative antitumor effects. Immunotherapy itself is a very broad type of treatment. It has several branches: therapeutic cancer vaccines, oncolytic virus therapy, checkpoint inhibitors, adoptive cell therapy, monoclonal antibodies, cytokines, and adjuvant immunotherapy - which all play a crucial role in the treatment of cancer. Evidence from past and ongoing clinical trials have proven that each branch of immunotherapy is effective, but its effectiveness can be enhanced with the combination of conventional cancer treatments. In particular, immunotherapy in conjunction with conventional cancer treatments has shown extraordinary results in the treatment of prostate cancer. With Sipuleucel-T being the only FDA approved immunotherapeutic cancer vaccine, researchers have found that its application leads to results suggesting that metastatic prostate cancer is no longer incurable. Immunotherapeutic approaches facilitated by gene therapy show great promise in treating multiple cancers; currently, we know that this approach has the potential to cure metastatic prostate cancer. With the definition of sustainability in mind, the information found clearly shows that the application of this therapy does in fact improve the quality of life and also holds great significance for future cancer treatment approaches. Figure 4 - Depicts the mechanisms of different conventional cancer treatments Combining Chemotherapy and Immunotherapy Until recently, it was unheard of to combine chemotherapy with immunotherapy because of the compromised immune system that results from chemotherapy treatment. Generally, it was believed that chemotherapy, when used in combination with a cancer vaccine, would have a negative effect on the patient. However, lately, a number of findings suggest that combining immuno- and chemotherapy results in better clinical responses in advanced cancer patients. Recent evidence also suggests that specific chemotherapeutic regimens can reduce the tumor growth rate in cancer patients when combined with specific cancer vaccines. The reason for this phenomenon may be that, as a result of the cell death caused by chemotherapy, the presentation of antigens furthers the activation of the immunotherapy induced T cell response, which ultimately leads to increased killing of cancer cells [14] [15]. Although there has been a surge of interest in the potential therapeutic benefits of regimens combining cancer vaccines with standard-of-care chemotherapy there are several important considerations. For example, the fact that employing a vaccine in combination with chemotherapy earlier rather than later in the disease treatment process shows significantly different results. Combining Radiation Therapy and Immunotherapy Although local control of the primary tumor is necessary for radiation therapy and can usually prevent metastasis, radiation generally fails to control pre-existing systemic disease, which may manifest as undetectable micro metastases. However, since radiation therapy and therefore irradiation ultimately leads to immunogenic death, this leaves cancer cells more vulnerable to killing by T cells from the therapeutic cancer vaccine, causing a more efficient response to even the surviving irradiated cancer cells. Interest in combining radiation and immune-based therapies for the treatment of cancer is growing in proportion to our understanding of the SOURCES [1] "Cancer Vaccines." 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Web. 03 Mar. 2017 https://clinicaltrials.gov/ct2/show/NCT01881867 [11] "Prostate Cancer Immunotherapy | CTCA." CancerCenter.com. N.p., 01 Jan. 0001. Web. 03 Mar. 2017 http://www.cancercenter.com/prostatecancer/immunotherapy/ [12] Drake, C. G. "Combination Immunotherapy Approaches." Annals of Oncology. Oxford University Press, 01 Sept. 2012. Web. 03 Mar. 2017. https://academic.oup.com/annonc/article/23/suppl_8/viii41/18 5508/Combination-immunotherapy-approaches [13] Center for Biologics Evaluation and Research. "Approved Products - Questions and Answers - Provenge." U S Food and Drug Administration Home Page. Center for Biologics Evaluation and Research, n.d. Web. 03 Mar. 2017. http://www.fda.gov/BiologicsBloodVaccines/CellularGeneTh erapyProducts/ApprovedProducts/ucm210037.htm [14] Hodge, James W., Andressa Ardiani, Benedetto Farsaci, Anna R. Kwilas, and Sofia Gameiro. "The Tipping Point for Combination Therapy: Cancer Vaccines with Radiation, Chemotherapy, or Targeted Small Molecule Inhibitors." Seminars in Oncology. U.S. National Library of Medicine, June 2012. Web. 03 Mar. 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356994/ [15] Hindawi. "Therapeutic Cancer Vaccines in Combination with Conventional Therapy." BioMed Research International. Hindawi Publishing Corporation, 29 June 2010. Web. 03 Mar.2017. https://www.hindawi.com/journals/bmri/2010/237623/ ACKNOWLEDGMENTS We would like to thank Barbara Edelman for helping us revise our work. Without her, the quality of this work would not have been professional. We would also like to thank various peers who helped us by giving insight on our topic area. We are also very grateful for Josh Zeleznick for taking time out of his day to help give instructions on how to approach this paper. And finally, we would like to thank Jacob Meadows for acting as a friend and advisor throughout the process of this paper. The completion and quality of this paper would’ve been compromised if it weren’t for all the people mentioned above. 8