Tumor Biol. DOI 10.1007/s13277-015-3491-2
REVIEW
New approaches for cancer immunotherapy Ayfer Karlitepe 1 & Ozgun Ozalp 2 & Cigir Biray Avci 2
Received: 13 April 2015 / Accepted: 23 April 2015 # International Society of Oncology and BioMarkers (ISOBM) 2015
Abstract Immunotherapy is a promising field that offers alternative methods for treatment of cancer. The current strategy consists of cancer vaccines, monoclonal antibodies, and cellular therapies. Cancer vaccines aim to eradicate cancer cells via immune system. Thus, they may attack these cells derived from any type of cancer, besides their role in preventing cancer. Lymphocytes and dendritic cells are often used in cellular therapy. In addition, monoclonal antibodies are designed to target specific antigens found in cancer cells. Currently, at least 12 clinically approved monoclonal antibodies are being used and many cancer vaccines are being developed with ongoing phase studies for cancer therapy. Relevant studies are focused on glioma and several other cancer types. Correspondingly, the combination of effective methods may enhance the efficacy of immunotherapy. It is thought that particularly immune checkpoint inhibitors will play a crucial role in immunotherapeutic approaches.
Keywords Cancer immunotherapy . Monoclonal antibody . Cancer vaccine . Glioma
* Cigir Biray Avci [email protected]
Introduction Cancer immunotherapy has emerged from developments in the fields of oncology and immunology during the last few centuries. In 1796, immunotherapy began with the success of Edward Jenner who performed the first immunization with cowpox to prevent smallpox. Emil Von Behring and Kitasato Shibasabo discovered the emergence of antitoxic blood serum diphtheria toxin by inoculating animals towards the end of the nineteenth century. Subsequently, Paul Ehrlich created Bmagic bullet^ concept; thereby, antibodies were used to target diseases in a specific manner. The production of monoclonal antibodies was not conducive for the treatment until Georges JF Köhler and Cesar Milstein produced hybridoma technology in 1975. In 1997, FDA approved the first antibody therapy with rituximab for the treatment of follicular lymphoma. Then, 11 different antibodies were approved including trastuzumab (1998), gemtuzumab ozogamicin (2000), alemtuzumab (2001), ibritumomab tiuxetan (2002), tositumomab (2003), cetuximab (2004), bevacizumab (2004), panitumumab (2006), ofatumumab (2009), ipilimumab (2011), and brentuximab vedotin (2011). The production of cancer vaccines came after the use of monoclonal antibodies. As our understanding of human immunology evolves, we have a potential to produce effective cancer vaccines. The first cell-based immunotherapy of cancer vaccine sipuleucel-T has been approved in 2010 for the treatment of prostate cancer [1].
1
Department of Medical Biochemistry, Medical School, Ege University, Izmir, Turkey
Applications in cancer immunotherapy
2
Department of Medical Biology, Medical School, Ege University, Izmir, Turkey
Strategies for cancer immunotherapy involve suitable methods activating the immune system in treatment of cancer.
Tumor Biol.
Immune system cells are targeted in order to destroy cancer cells. This approach may be achieved by three methods [2]. 1. The first method is based on specific antibodies for cancer therapy. 2. The second method is based on vaccination produced using the protein in cancer patients. 3. The third method is performed by transferring immune system cells such as cytotoxic T lymphocytes or dendritic cells to the patient [2].
Monoclonal antibodies These are artificial versions of immune system proteins. Antibodies may be very useful in treatment of cancer because they are designed to attack very specific regions of cancer cells [3]. Cancer vaccines Vaccines are agents that are intended to overcome specific diseases by generating an immune response. Overall, they are thought to be responsible for the prevention of infection in healthy people. However, some vaccines may treat or prevent cancer [3]. Nonspecific immunotherapy Although this type of treatment aims to support the immune system nonspecifically, it could result in an action against cancer cells [3]. Monoclonal antibodies Many copies of particular antibodies can be generated in the laboratory. These are known as monoclonal antibodies (mAbs or MoAbs) and designed to target specific antigens in cancer. Thus, these antibodies may be useful for combating the disease. Current monoclonal antibodies include certain types related to treatment of cancer and several diseases. Although the main advantage of these drugs is not very specific, side effects may be mild in contrast to other types of cancer treatment. In this regard, researchers must consider whether the correct antigen should be specified to be attacked. In addition, it has been proven that mAbs are more useful against some cancers than other therapeutics. Food and Drug Administration has applied numerous specific mAbs to treat types of cancers during the last 15 years in the USA [3]. Types of monoclonal antibodies There are two types of monoclonal antibodies used for treatment of cancer. Naked antibodies are not supposed to be combined with any drugs. Therefore, this type of mAb is able to function alone. Conjugated mAbs are involved in chemotherapy drug, radioactive particles, or toxins. These mABs function as a tool which leads these agents directly into cancer cells [3].
Cancer vaccines Virus vaccines differ from vaccines used in treatment of cancer. Cancer vaccines aim to eradicate cancer cells by attacking them, besides their role in preventing cancer. Cancer therapy vaccines contain cancer cells, some parts of cancer cells, or purified antigens to enhance the immune response against cancer cells. In addition, the immune system has its own memory cells which allow a repetitive immunity [4]. Currently, therapeutic vaccines are promising in order to eradicate cancer cells. Although the combination of cancer vaccines and novel agents may be efficient in practical use, obstacles regarding the determination of favorable tumor antigens and suppression of immune system should be eliminated [5]. Nonspecific immunotherapy This type of immunotherapy approach is essential for mentioning lymphocytes and dendritic cells. Adoptive T cell therapy is a type of passive immunization of transplantation with the T cell. Receptors on the surface of T cells are activated when they meet proteins called as antigens. Specific immune cells known as inflammatory cells or antigen-presenting cells (APCs) exist in normal tissues and tumor-infiltrating lymphocytes (TILs) that have been known as tumor tissues. They are mobilized as tumor antigens to T cells by the presence of antigen-presenting cells such as dendritic cells. Even though these cells have a capacity to attack against tumor cells, the tumor environment is highly immunosuppressive; thus, tumor blocks of immune-mediated death. Due to the fact that several ways are available to gain tumortargeted T cells, tumor antigen-specific T cells may be obtained from tumor samples or T cells may be modified genetically. Activation of these cells is performed by ex vivo transferring. Although studies on this type of therapy have a promising improvement, an adoptive T cell therapy is not available yet. Tumor-specific T cells must be used specifically for the treatment of tumor depending on specific antigens, tumor stroma, or vasculature [6]. Examples of tumor-specific antigens are composed of tissue differentiation antigens, mutant protein antigens, oncogenic viral antigens, cancer testis antigens, and stromal vascular or specific antigens. Tissue differentiation antigens are unique for each particular tissue type. This antigen-specific T cell targets several types of cells including cancer cells and normal cell antigens (carcinoembryonic antigen; CEA). Mutant proteins as antigens constitute a specific property for cancer cells, due to the fact that normal cells should not involve these proteins. While normal cell indicates normal protein antigens on MHC molecules, cancer cell indicates the mutant version. T cells may distinguish these two cells from each other; thus, these are able to target cancer cells. Some of the viral proteins are involved in cancer progression
Tumor Biol.
(oncogenesis); hence, the specific viral antigens for T cells could be used to attack the inflammatory cells which include cancer cells [6]. Dendritic cells (DC) combine the hereditary immune system with the adaptive immune response. When the hereditary immune system is activated, dendritic cells detect this action as a Bdanger^, and they stop uptake of antigen and move to the local lymph nodes. They provide the tasks of antigen to specific T lymphocytes. There are two general methods to achieve this goal: ex vivo and in vivo activation. Ex vivo methods are utilized in order for generating dendritic cells through a culture of circulating monocytes. Also, dendritic cells could be obtained from the circulating CD34+ hematopoietic stem cells (HSCS). FDA approved the reliability of ex vivo-activated immunotherapy on the treatment of metastatic prostate [7].
New approaches for glioma immunotherapy In Japan, a study was performed on investigating autoantibodies in plasma of patients suffering from glioma. Then, anti-vascular endothelial growth factor receptor 2 (antiVEGFR2) autoantibodies were defined and their functional values were estimated. Mononuclear cells and plasma were obtained via peripheral blood of 17 glioma patients for B cell acquirement. Complementary DNA derived from B cells was transfected with the plasmid. Then, the B cell-based monoclonal antibody genes were amplified by PCR. Antibodies raised against VEGFR2 were described with cellular staining by using PCR and surface plasmon resonance analysis. AntiVEGFR2 antibodies have been shown to use B cells in accordance with these analysis results [8]. The information was provided through a review on immunovirotherapy published in the USA. Oncolytic herpes simplex virus (oHSV) was used for the application of immunovirotherapy. Genetically engineered oHSV cells were programmed to replicate in tumor cells. Thus, normal cells could protect themselves from the virus. The virus that is transferred to mice via intracranial injection begins to replicate in oHSV-infected tumor cell causing death of tumor cell. The immune system was activated by the tumor antigens that spread out from the tumor microenvironment. Newly generated viruses are able to infect the potential tumor cells. As a result, this method was determined as a promising approach for glioma patients [9]. GL261 cells were implanted into cerebral hemispheres in order to create glioma models. Splenocytes were isolated from mouse to obtain antibodies 4 days after implantation. GL261 cells and the conventional antibody A2B5 were incubated together, and cells were implanted to the intracranium of rats. The dendritic cells (DC) were isolated from the bone marrow by specific methods. GL261 cell lysate containing A2B5 and DC
were injected subcutaneously into mice. Consequently, it was found that this application could prevent glioma formation [10]. Thaci et al. studied the impact of interleukin-12 (IL12) on glioma. IL12 gene was transfected with a plasmid on GL261 glioma cell line. Glioma model has been developed in mice, and IL12 gene transfected cells were injected to the intracranium. Results showed that IL12 induced the formation of dendritic cells, CD8 and CD4 T cells, and NK cells in the tumor microenvironment [11]. A study performed in Sweden proved that cyclooxygenase2 (COX2) indicated the inhibition of brain tumors. It has been reported that this enzyme catalyzes prostaglandin E2 (PGE2) which is an immunocompromised protein. Furthermore, GL261 brain tumor cell line was programmed to synthesize granulocyte-macrophage colony-stimulating factor (GMCSF) and these cells were injected into mice. The COX2 inhibitors such as parecoxib or valdecoxib were applied intratumoral following tumor inoculation. As a result, it was determined that the amount of PGE2 protein decreased and the combined treatment with GMCSF increased the answer to the T cells [12]. Thaci et al. published a review associated with interleukin13 receptor α chain variant 2 (IL13Rα2) on glioma. The research team pointed out that their study is at a preclinical phase. Principally, IL13 is responsible for regulating immune responses and immune microenvironment in both normal and cancerous conditions. IL13 is connected to IL13Rα2 with a high affinity in the process of carcinogenesis. However, this study reported that the expression of the receptor elevates malignancy degree of glioma. In addition, IL13Rα2-targeted immunotherapy strategy contains bacterial toxins, nanoparticles, and oncolytic viruses [13]. Due to the current treatment of glioma that could not prolong the survival of patients efficiently, immunotherapy may provide an encouraging alternative to cure this type of tumor. Therefore, it has been reported that A disintegrin and metalloproteinase (ADAM) proteases 10 and 17 which are expressed on the cell surface of glioma-initiating cells might be targeted to stimulate immune response in glioma. Then, the role of ADAM10 and ADAM17 in modulation of immunogenicity of GIC was clarified via NKG2D receptor-ligand system. As a result, in order to be recognized by NK cells, ADAM proteases were investigated by using specific inhibitors [14]. The future of immunotherapy Despite all the scientific developments, practical applications in cancer immunotherapy remain still unsatisfied. However, recent results showed that cancer immunotherapy was supported by biopharmaceutical industry due to its promising therapeutic strategy. For a long time during the twentieth century, targeting the immune system has been at the forefront in treatment of cancer. In theory, it was estimated to inactivate
Tumor Biol.
oncogenes and other mutations via the immune system (14). In 2010, the public awareness about cancer immunotherapy was increased due to the FDA approval of the therapeutics called as sipuleucel-T for the treatment of prostate cancer. Then, the development of ipilimumab provided benefits for the treatment of melanoma [15]. In the future, researchers will struggle to identify novel synergistic combinations and reduce toxicity. Due to tumor antigens are specific for each type of tumor, suitable tumor antigens need to be defined for targeted immunotherapies. Also, the identification of biomarkers will provide essential benefits in the prediction of survival [5]. In addition, histone deacetylase (HDAC) inhibitors may have a clinical potential to be combined with immunotherapy. Recent studies reported that HDAC inhibitors could promote tumor-associated antigen expression and act synergistic with cancer immunotherapy. These inhibitors are also able to induce apoptosis and stimulate tumor cell recognition by NK and T cells; thereby, tumor cells can be targeted by immune cells [16]. As a result, the novel combinations of immune checkpoint inhibitors and therapeutic vaccines have enhanced the efficacy of cancer immunotherapy. In addition to radiotherapy and chemotherapy, targeted agents will play a key role in generating a less toxic treatment [5].
3. 4. 5. 6. 7. 8.
9. 10.
11.
12.
13.
14.
References 1.
Strebhardt K, Ullrich A. Paul Ehrlich’s magic bullet concept: 100 years of progress. Nat Rev Cancer. 2008;8(6):473–80. 2. Çağrı Ş, Halit C, Kenan İ. Kanser İmmün Terapi ve MonoklonalAntikorlar. Fırat Üniv Sağlık Bilimleri Tıp Derg. 2013;27(2):105–10.
15. 16.
Old LJ, Scott AM, Wolchok JD. Antibody therapy of cancer. Nat Rev Cancer. 2012;12(4):278–87. Andrea S, Hans S, Mary P. Specificity in cancer immunotherapy. Semin Immunol. 2008;20(5):276–85. Rini B. Future approaches in immunotherapy. Semin Immunol. 2014;5:30–40. June CH. Adoptive T cell therapy for cancer in the clinic. J Clin Invest. 2007;117(6):1466–76. Harris TJ, Drake CG. Primer on tumor immunology and cancer immunotherapy. J Immunother Cancer. 2013;1:12. Akiko K, Akira I, Chie O, Ken Y, Koichi M, Masaru K, et al. Antivascular endothelial growth factor receptor (VEGFR) 2 autoantibody identification in glioblastoma patient using single B cell-based antibody gene cloning. Immunol Lett. 2014;159:15–22. Hiroaki W, Jianfang N, Samuel D. Immunovirotherapy for glioblastoma. Cell Cycle. 2014;13(2):175–6. Ming X, Ping Z, Wei H, Yu Y, Zhebao W. Mouse glioma immunotherapy mediated by A2B5+ GL261 cell lysate-pulsed dendritic cells. J Neuro-Oncol. 2014;116:497–504. Thaci B, Ahmed AU, Ulasov IV, Wainwright DA, Nigam P, Auffinger B, Tobias AL, Han Y, Zhang L, Moon KS, Lesniak MS. Depletion of myeloid-derived suppressor cells during interleukin-12 immunogene therapy does not confer a survival advantage in experimental malignant glioma. Cancer Gene Ther. 2014;21:38–44. Anna D, Edward V, Emma S, Sofia E. Intratumoral COX-2 inhibition enhances GM-CSF immunotherapy against established mouse GL261 brain tumors. Int J Cancer. 2014;134:2748–53. Bart T, Brown CE, Emanuela B, Katherine W, Prakash S, Sadhak S. Significance of interleukin-13 receptor alpha 2-targeted glioblastoma therapy. Neuro-Oncology. 2014;16(10):1304–12. Alexander S, Fabian W, Isabel T, Michael W. A disintegrin and metalloproteinases 10 and 17 modulate the immunogenicity of glioblastoma-initiating cells. Neuro-Oncology. 2014;16(3):382–91. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480–9. Kroesen M, Gielen P, Brok IC, Armandari I, Hoogerbrugge PM, Adema GJ. HDAC inhibitors and immunotherapy; a double edged sword. Oncotarget. 2014;5(16):6558–72.
REVIEW
New approaches for cancer immunotherapy Ayfer Karlitepe 1 & Ozgun Ozalp 2 & Cigir Biray Avci 2
Received: 13 April 2015 / Accepted: 23 April 2015 # International Society of Oncology and BioMarkers (ISOBM) 2015
Abstract Immunotherapy is a promising field that offers alternative methods for treatment of cancer. The current strategy consists of cancer vaccines, monoclonal antibodies, and cellular therapies. Cancer vaccines aim to eradicate cancer cells via immune system. Thus, they may attack these cells derived from any type of cancer, besides their role in preventing cancer. Lymphocytes and dendritic cells are often used in cellular therapy. In addition, monoclonal antibodies are designed to target specific antigens found in cancer cells. Currently, at least 12 clinically approved monoclonal antibodies are being used and many cancer vaccines are being developed with ongoing phase studies for cancer therapy. Relevant studies are focused on glioma and several other cancer types. Correspondingly, the combination of effective methods may enhance the efficacy of immunotherapy. It is thought that particularly immune checkpoint inhibitors will play a crucial role in immunotherapeutic approaches.
Keywords Cancer immunotherapy . Monoclonal antibody . Cancer vaccine . Glioma
* Cigir Biray Avci [email protected]
Introduction Cancer immunotherapy has emerged from developments in the fields of oncology and immunology during the last few centuries. In 1796, immunotherapy began with the success of Edward Jenner who performed the first immunization with cowpox to prevent smallpox. Emil Von Behring and Kitasato Shibasabo discovered the emergence of antitoxic blood serum diphtheria toxin by inoculating animals towards the end of the nineteenth century. Subsequently, Paul Ehrlich created Bmagic bullet^ concept; thereby, antibodies were used to target diseases in a specific manner. The production of monoclonal antibodies was not conducive for the treatment until Georges JF Köhler and Cesar Milstein produced hybridoma technology in 1975. In 1997, FDA approved the first antibody therapy with rituximab for the treatment of follicular lymphoma. Then, 11 different antibodies were approved including trastuzumab (1998), gemtuzumab ozogamicin (2000), alemtuzumab (2001), ibritumomab tiuxetan (2002), tositumomab (2003), cetuximab (2004), bevacizumab (2004), panitumumab (2006), ofatumumab (2009), ipilimumab (2011), and brentuximab vedotin (2011). The production of cancer vaccines came after the use of monoclonal antibodies. As our understanding of human immunology evolves, we have a potential to produce effective cancer vaccines. The first cell-based immunotherapy of cancer vaccine sipuleucel-T has been approved in 2010 for the treatment of prostate cancer [1].
1
Department of Medical Biochemistry, Medical School, Ege University, Izmir, Turkey
Applications in cancer immunotherapy
2
Department of Medical Biology, Medical School, Ege University, Izmir, Turkey
Strategies for cancer immunotherapy involve suitable methods activating the immune system in treatment of cancer.
Tumor Biol.
Immune system cells are targeted in order to destroy cancer cells. This approach may be achieved by three methods [2]. 1. The first method is based on specific antibodies for cancer therapy. 2. The second method is based on vaccination produced using the protein in cancer patients. 3. The third method is performed by transferring immune system cells such as cytotoxic T lymphocytes or dendritic cells to the patient [2].
Monoclonal antibodies These are artificial versions of immune system proteins. Antibodies may be very useful in treatment of cancer because they are designed to attack very specific regions of cancer cells [3]. Cancer vaccines Vaccines are agents that are intended to overcome specific diseases by generating an immune response. Overall, they are thought to be responsible for the prevention of infection in healthy people. However, some vaccines may treat or prevent cancer [3]. Nonspecific immunotherapy Although this type of treatment aims to support the immune system nonspecifically, it could result in an action against cancer cells [3]. Monoclonal antibodies Many copies of particular antibodies can be generated in the laboratory. These are known as monoclonal antibodies (mAbs or MoAbs) and designed to target specific antigens in cancer. Thus, these antibodies may be useful for combating the disease. Current monoclonal antibodies include certain types related to treatment of cancer and several diseases. Although the main advantage of these drugs is not very specific, side effects may be mild in contrast to other types of cancer treatment. In this regard, researchers must consider whether the correct antigen should be specified to be attacked. In addition, it has been proven that mAbs are more useful against some cancers than other therapeutics. Food and Drug Administration has applied numerous specific mAbs to treat types of cancers during the last 15 years in the USA [3]. Types of monoclonal antibodies There are two types of monoclonal antibodies used for treatment of cancer. Naked antibodies are not supposed to be combined with any drugs. Therefore, this type of mAb is able to function alone. Conjugated mAbs are involved in chemotherapy drug, radioactive particles, or toxins. These mABs function as a tool which leads these agents directly into cancer cells [3].
Cancer vaccines Virus vaccines differ from vaccines used in treatment of cancer. Cancer vaccines aim to eradicate cancer cells by attacking them, besides their role in preventing cancer. Cancer therapy vaccines contain cancer cells, some parts of cancer cells, or purified antigens to enhance the immune response against cancer cells. In addition, the immune system has its own memory cells which allow a repetitive immunity [4]. Currently, therapeutic vaccines are promising in order to eradicate cancer cells. Although the combination of cancer vaccines and novel agents may be efficient in practical use, obstacles regarding the determination of favorable tumor antigens and suppression of immune system should be eliminated [5]. Nonspecific immunotherapy This type of immunotherapy approach is essential for mentioning lymphocytes and dendritic cells. Adoptive T cell therapy is a type of passive immunization of transplantation with the T cell. Receptors on the surface of T cells are activated when they meet proteins called as antigens. Specific immune cells known as inflammatory cells or antigen-presenting cells (APCs) exist in normal tissues and tumor-infiltrating lymphocytes (TILs) that have been known as tumor tissues. They are mobilized as tumor antigens to T cells by the presence of antigen-presenting cells such as dendritic cells. Even though these cells have a capacity to attack against tumor cells, the tumor environment is highly immunosuppressive; thus, tumor blocks of immune-mediated death. Due to the fact that several ways are available to gain tumortargeted T cells, tumor antigen-specific T cells may be obtained from tumor samples or T cells may be modified genetically. Activation of these cells is performed by ex vivo transferring. Although studies on this type of therapy have a promising improvement, an adoptive T cell therapy is not available yet. Tumor-specific T cells must be used specifically for the treatment of tumor depending on specific antigens, tumor stroma, or vasculature [6]. Examples of tumor-specific antigens are composed of tissue differentiation antigens, mutant protein antigens, oncogenic viral antigens, cancer testis antigens, and stromal vascular or specific antigens. Tissue differentiation antigens are unique for each particular tissue type. This antigen-specific T cell targets several types of cells including cancer cells and normal cell antigens (carcinoembryonic antigen; CEA). Mutant proteins as antigens constitute a specific property for cancer cells, due to the fact that normal cells should not involve these proteins. While normal cell indicates normal protein antigens on MHC molecules, cancer cell indicates the mutant version. T cells may distinguish these two cells from each other; thus, these are able to target cancer cells. Some of the viral proteins are involved in cancer progression
Tumor Biol.
(oncogenesis); hence, the specific viral antigens for T cells could be used to attack the inflammatory cells which include cancer cells [6]. Dendritic cells (DC) combine the hereditary immune system with the adaptive immune response. When the hereditary immune system is activated, dendritic cells detect this action as a Bdanger^, and they stop uptake of antigen and move to the local lymph nodes. They provide the tasks of antigen to specific T lymphocytes. There are two general methods to achieve this goal: ex vivo and in vivo activation. Ex vivo methods are utilized in order for generating dendritic cells through a culture of circulating monocytes. Also, dendritic cells could be obtained from the circulating CD34+ hematopoietic stem cells (HSCS). FDA approved the reliability of ex vivo-activated immunotherapy on the treatment of metastatic prostate [7].
New approaches for glioma immunotherapy In Japan, a study was performed on investigating autoantibodies in plasma of patients suffering from glioma. Then, anti-vascular endothelial growth factor receptor 2 (antiVEGFR2) autoantibodies were defined and their functional values were estimated. Mononuclear cells and plasma were obtained via peripheral blood of 17 glioma patients for B cell acquirement. Complementary DNA derived from B cells was transfected with the plasmid. Then, the B cell-based monoclonal antibody genes were amplified by PCR. Antibodies raised against VEGFR2 were described with cellular staining by using PCR and surface plasmon resonance analysis. AntiVEGFR2 antibodies have been shown to use B cells in accordance with these analysis results [8]. The information was provided through a review on immunovirotherapy published in the USA. Oncolytic herpes simplex virus (oHSV) was used for the application of immunovirotherapy. Genetically engineered oHSV cells were programmed to replicate in tumor cells. Thus, normal cells could protect themselves from the virus. The virus that is transferred to mice via intracranial injection begins to replicate in oHSV-infected tumor cell causing death of tumor cell. The immune system was activated by the tumor antigens that spread out from the tumor microenvironment. Newly generated viruses are able to infect the potential tumor cells. As a result, this method was determined as a promising approach for glioma patients [9]. GL261 cells were implanted into cerebral hemispheres in order to create glioma models. Splenocytes were isolated from mouse to obtain antibodies 4 days after implantation. GL261 cells and the conventional antibody A2B5 were incubated together, and cells were implanted to the intracranium of rats. The dendritic cells (DC) were isolated from the bone marrow by specific methods. GL261 cell lysate containing A2B5 and DC
were injected subcutaneously into mice. Consequently, it was found that this application could prevent glioma formation [10]. Thaci et al. studied the impact of interleukin-12 (IL12) on glioma. IL12 gene was transfected with a plasmid on GL261 glioma cell line. Glioma model has been developed in mice, and IL12 gene transfected cells were injected to the intracranium. Results showed that IL12 induced the formation of dendritic cells, CD8 and CD4 T cells, and NK cells in the tumor microenvironment [11]. A study performed in Sweden proved that cyclooxygenase2 (COX2) indicated the inhibition of brain tumors. It has been reported that this enzyme catalyzes prostaglandin E2 (PGE2) which is an immunocompromised protein. Furthermore, GL261 brain tumor cell line was programmed to synthesize granulocyte-macrophage colony-stimulating factor (GMCSF) and these cells were injected into mice. The COX2 inhibitors such as parecoxib or valdecoxib were applied intratumoral following tumor inoculation. As a result, it was determined that the amount of PGE2 protein decreased and the combined treatment with GMCSF increased the answer to the T cells [12]. Thaci et al. published a review associated with interleukin13 receptor α chain variant 2 (IL13Rα2) on glioma. The research team pointed out that their study is at a preclinical phase. Principally, IL13 is responsible for regulating immune responses and immune microenvironment in both normal and cancerous conditions. IL13 is connected to IL13Rα2 with a high affinity in the process of carcinogenesis. However, this study reported that the expression of the receptor elevates malignancy degree of glioma. In addition, IL13Rα2-targeted immunotherapy strategy contains bacterial toxins, nanoparticles, and oncolytic viruses [13]. Due to the current treatment of glioma that could not prolong the survival of patients efficiently, immunotherapy may provide an encouraging alternative to cure this type of tumor. Therefore, it has been reported that A disintegrin and metalloproteinase (ADAM) proteases 10 and 17 which are expressed on the cell surface of glioma-initiating cells might be targeted to stimulate immune response in glioma. Then, the role of ADAM10 and ADAM17 in modulation of immunogenicity of GIC was clarified via NKG2D receptor-ligand system. As a result, in order to be recognized by NK cells, ADAM proteases were investigated by using specific inhibitors [14]. The future of immunotherapy Despite all the scientific developments, practical applications in cancer immunotherapy remain still unsatisfied. However, recent results showed that cancer immunotherapy was supported by biopharmaceutical industry due to its promising therapeutic strategy. For a long time during the twentieth century, targeting the immune system has been at the forefront in treatment of cancer. In theory, it was estimated to inactivate
Tumor Biol.
oncogenes and other mutations via the immune system (14). In 2010, the public awareness about cancer immunotherapy was increased due to the FDA approval of the therapeutics called as sipuleucel-T for the treatment of prostate cancer. Then, the development of ipilimumab provided benefits for the treatment of melanoma [15]. In the future, researchers will struggle to identify novel synergistic combinations and reduce toxicity. Due to tumor antigens are specific for each type of tumor, suitable tumor antigens need to be defined for targeted immunotherapies. Also, the identification of biomarkers will provide essential benefits in the prediction of survival [5]. In addition, histone deacetylase (HDAC) inhibitors may have a clinical potential to be combined with immunotherapy. Recent studies reported that HDAC inhibitors could promote tumor-associated antigen expression and act synergistic with cancer immunotherapy. These inhibitors are also able to induce apoptosis and stimulate tumor cell recognition by NK and T cells; thereby, tumor cells can be targeted by immune cells [16]. As a result, the novel combinations of immune checkpoint inhibitors and therapeutic vaccines have enhanced the efficacy of cancer immunotherapy. In addition to radiotherapy and chemotherapy, targeted agents will play a key role in generating a less toxic treatment [5].
3. 4. 5. 6. 7. 8.
9. 10.
11.
12.
13.
14.
References 1.
Strebhardt K, Ullrich A. Paul Ehrlich’s magic bullet concept: 100 years of progress. Nat Rev Cancer. 2008;8(6):473–80. 2. Çağrı Ş, Halit C, Kenan İ. Kanser İmmün Terapi ve MonoklonalAntikorlar. Fırat Üniv Sağlık Bilimleri Tıp Derg. 2013;27(2):105–10.
15. 16.
Old LJ, Scott AM, Wolchok JD. Antibody therapy of cancer. Nat Rev Cancer. 2012;12(4):278–87. Andrea S, Hans S, Mary P. Specificity in cancer immunotherapy. Semin Immunol. 2008;20(5):276–85. Rini B. Future approaches in immunotherapy. Semin Immunol. 2014;5:30–40. June CH. Adoptive T cell therapy for cancer in the clinic. J Clin Invest. 2007;117(6):1466–76. Harris TJ, Drake CG. Primer on tumor immunology and cancer immunotherapy. J Immunother Cancer. 2013;1:12. Akiko K, Akira I, Chie O, Ken Y, Koichi M, Masaru K, et al. Antivascular endothelial growth factor receptor (VEGFR) 2 autoantibody identification in glioblastoma patient using single B cell-based antibody gene cloning. Immunol Lett. 2014;159:15–22. Hiroaki W, Jianfang N, Samuel D. Immunovirotherapy for glioblastoma. Cell Cycle. 2014;13(2):175–6. Ming X, Ping Z, Wei H, Yu Y, Zhebao W. Mouse glioma immunotherapy mediated by A2B5+ GL261 cell lysate-pulsed dendritic cells. J Neuro-Oncol. 2014;116:497–504. Thaci B, Ahmed AU, Ulasov IV, Wainwright DA, Nigam P, Auffinger B, Tobias AL, Han Y, Zhang L, Moon KS, Lesniak MS. Depletion of myeloid-derived suppressor cells during interleukin-12 immunogene therapy does not confer a survival advantage in experimental malignant glioma. Cancer Gene Ther. 2014;21:38–44. Anna D, Edward V, Emma S, Sofia E. Intratumoral COX-2 inhibition enhances GM-CSF immunotherapy against established mouse GL261 brain tumors. Int J Cancer. 2014;134:2748–53. Bart T, Brown CE, Emanuela B, Katherine W, Prakash S, Sadhak S. Significance of interleukin-13 receptor alpha 2-targeted glioblastoma therapy. Neuro-Oncology. 2014;16(10):1304–12. Alexander S, Fabian W, Isabel T, Michael W. A disintegrin and metalloproteinases 10 and 17 modulate the immunogenicity of glioblastoma-initiating cells. Neuro-Oncology. 2014;16(3):382–91. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480–9. Kroesen M, Gielen P, Brok IC, Armandari I, Hoogerbrugge PM, Adema GJ. HDAC inhibitors and immunotherapy; a double edged sword. Oncotarget. 2014;5(16):6558–72.
