Nadiah Abu; Nurul Ainaa Adilah Rus Bakarurraini; Siti Nurmi Nasir; Muhiddin Ishak; Rashidah Baharuddin; Rahman Jamal; Nurul Syakima Ab Mutalib
Abstract
Background: Cancer testis antigens (CTAs) are a class of immune-stimulating antigens often overexpressed in many types of cancers. The usage of the CTAs as immunotherapy targets have been widely investigated in different cancers including melanoma, hematological malignancies, and colorectal cancer. Studies ...
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Background: Cancer testis antigens (CTAs) are a class of immune-stimulating antigens often overexpressed in many types of cancers. The usage of the CTAs as immunotherapy targets have been widely investigated in different cancers including melanoma, hematological malignancies, and colorectal cancer. Studies have indicated that the epigenetic regulation of the CTAs such as the methylation status may affect the expression of the CTAs. However, the report on the methylation status of the CTAs is conflicting. The general methylation profile of the CTAs, especially in colorectal cancer, is still elusive.Objective: To determine the methylation profile of the selected CTAs in our colorectal cancer patients.Methods: A total of 54 pairs of colorectal cancer samples were subjected to DNA methylation profiling using the Infinium Human Methylation 450K bead chip.Results: We found that most of the CTAs were hypomethylated, and CCNA1 and TMEM108 genes were among the few CTAs that were hypermethylated.Conclusion: Overall, our brief report has managed to show the overall methylation profile in over the 200 CTAs in colorectal cancer and this could be used for further refining any immunotherapy targets.
Samaneh Arab; Masoumeh Motamedi; Jamshid Hadjati
Abstract
Background: Dendritic cells (DCs) contribute essentially to the outset and course of immune responses. So in patients with malignancy, there have been considerable interests in use of these cells in different interventions. Objective: To evaluate the impact of Leishmania major’s components ...
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Background: Dendritic cells (DCs) contribute essentially to the outset and course of immune responses. So in patients with malignancy, there have been considerable interests in use of these cells in different interventions. Objective: To evaluate the impact of Leishmania major’s components on DC maturation and their use as a therapeutic agent against tumor cells. Methods: The cancer model was induced by injection of WEHI-164 cells (BALB/c derived fibrosarcoma cell line) subcutaneously in the right flank of animals. Bone-marrow derived DCs (BMDCs) were cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4. After 5 days, tumor lysate, Leishmania major’s lysate, and Lipopolysaccharide (LPS) were added to the culture and incubated for 2 days. IL-12 production in DCs was measured by ELISA. For Immunotherapy, Mice received DCs subcutaneously around the tumor site. Two weeks after DCs injection, cytotoxicity assay and infiltration of CD8+ lymphocytes were evaluated. Results: Our results showed that immunotherapy with dendritic cells exposed to Leishmania extract led to producing a higher amount of IL-12, compare to the control group. A considerable increment in specific cytotoxic T cells activity, diminished tumor growth rate and improved survival of immunized animals were seen. Conclusion: This study indicates that the use of Leishmania major extract, as well as LPS, can enhance the efficiency of DC-based vaccines and provides a basis for the use of Leishmania major in DC-targeted clinical therapies.
Reza Hosseini-Ghatar; Tahereh Soltantoyeh; Motahareh Bahadori; Jalal Khoshnoodi; Forough Golsaz-Shirazi; Mahmood Jeddi-Tehrani; Mohammad Mehdi Amiri; Fazel Shokri
Volume 14, Issue 3 , September 2017, , Pages 200-214
Abstract
Background: Human epidermal growth factor receptor 2 (HER2) has a crucial role in several malignancies. The extracellular domain of HER2 (HER2-ECD) has been extensively employed as an important target in passive and active immunotherapy. Isolated recombinant prokaryotic HER2-ECD subdomains were previously ...
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Background: Human epidermal growth factor receptor 2 (HER2) has a crucial role in several malignancies. The extracellular domain of HER2 (HER2-ECD) has been extensively employed as an important target in passive and active immunotherapy. Isolated recombinant prokaryotic HER2-ECD subdomains were previously found to be ineffective in inducing anti-tumor antibody response. Objective: To employ recombinant eukaryotic HER2-ECD subdomains to raise anti-HER2 antibodies and determine their anti-tumor activity in vitro. Methods: Two paired subdomains of HER2-ECD (DI+II and DIII+IV), representing Pertuzumab and Trastuzumab binding domains, respectively, along with the full extracellular domain of HER2 were generated in CHO-K1 cells. Polyclonal antibodies were raised against these subdomains and characterized using ELISA, flow cytometry, and immunoblot and their anti-tumor activity was assessed by XTT assay. The cross-reactivity of these antibodies was specified along with other members of the human HER family. Results: Similar to Trastuzumab and anti-HER2-ECD antibody, anti-DI+II and DIII+IV polyclonal antibodies reacted with recombinant HER2-ECD and native HER2 expressed on tumor cells. These two polyclonal antibodies were able to inhibit the binding of Pertuzumab and Trastuzumab to HER2, respectively, and did not cross-react with other members of HER family. These antibodies were able to inhibit tumor cell growth in vitro, similar to Trastuzumab. Conclusion: The high immunogenicity of human HER2 DI+II and DIII+IV subdomains in rabbits and the tumor inhibitory activity of the purified specific antibodies imply that they might be suitable for active immunotherapy in formulation with appropriate adjuvants and in combination with other HER2 specific therapeutics.
Abdolkarim Sheikhi; Abdollah Jafarzadeh; Parviz Kokhaei; Mohammad Hojjat-Farsangi
Volume 13, Issue 3 , September 2016, , Pages 148-166
Abstract
Cancer immunotherapy (passive or active) involves treatments which promote the ability of the immune system to fight tumor cells. Several types of immunotherapeutic agents, such as monoclonal antibodies, immune checkpoint inhibitors, non-specific immunomodulatory agents, and cancer vaccines are currently ...
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Cancer immunotherapy (passive or active) involves treatments which promote the ability of the immune system to fight tumor cells. Several types of immunotherapeutic agents, such as monoclonal antibodies, immune checkpoint inhibitors, non-specific immunomodulatory agents, and cancer vaccines are currently under intensive investigation in preclinical and clinical trials. Cancer vaccines induce permanent activation of the immune system and may be considered the most promising method for cancer treatment, especially in combination with other agents of passive immunotherapy. Among various approaches to cancer vaccines, whole tumor cell vaccines have been attracting attention for several years. Despite their low to moderate clinical effects, these vaccines have numerous advantages. Their ability to generate immune responses against tumor-associated antigens reduces the possibility for tumor cells to escape and facilitates the development of “off-the-shelf” allogeneic tumor vaccines. Understanding the reciprocal interactions between tumor cells and leukocytes is a key to harness the full potential of whole cell vaccination. Cytokines are considered as potent immunomodulatory molecules which behave as adjuvants in whole tumor cell vaccines. Improved mechanistic understanding of key cytokines in tumor immunity will serve as a resource for rational design of whole cell cancer vaccines. Although there are several reports about the use of different immunostimulatory cytokines as adjuvants, interleukin (IL)-12 appears to have superior effects compared to other cytokines. This review describes the effects of IL-12 compared to other immunomodulatory cytokines, such as IL-2 and IL-15, and highlights its application in whole cell tumor vaccination.
Maryam Azimi Mohamadabadi; Zuhair Mohammad Hassan; Ahmad Zavaran Hosseini; Mehrdad Gholamzad; Shekoofe Noori; Mehdi Mahdavi; Hamidreza Maroof
Volume 10, Issue 3 , September 2013, , Pages 139-149
Abstract
Background: Chemo-immunotherapy is one of the new achievements for treatment of cancer, by which the success of anti-cancer therapy can be increased. In vitro studies have been shown that Arteether (ARE) induces apoptosis in tumor cells, but not in normal cells. Objective: To investigate the cytotoxic ...
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Background: Chemo-immunotherapy is one of the new achievements for treatment of cancer, by which the success of anti-cancer therapy can be increased. In vitro studies have been shown that Arteether (ARE) induces apoptosis in tumor cells, but not in normal cells. Objective: To investigate the cytotoxic and immunomodulatory properties of Arteether in-vivo and in-vitro. Methods: In this study, we used MTT assay for evaluation of cytotoxicity of Arteether on tumor cell line and Peripheral Blood Mononuclear Cells (PBMCs) from healthy individuals. Balb/c mice were subcutaneously transplanted with tumor tissue taken from Spontaneous Mouse Mammary Tumor (SMMT) bearing female mice. Arteether was administered to breast tumor-bearing Balb/c mice at a dose of 6 mg/kg/day intraperitoneally. Tumor sizes, lymphocyte proliferation, cytokines production, and the percentage of splenic T-reg cells were measured. Results: We observed that ARE could reduce the cell growth of 4T1 cell line in a dose-dependent manner but it had no cytotoxic effect on the growth of peripheral blood lymphocytes. ARE administered intraperitoneally to tumor-bearing Balb/c mice could reduce the tumor growth rate and splenic T-reg cells. No difference in the IFN-γ, IL-10 and IL-4 production was observed between tumor antigenstimulated splenocytes of mice treated with ARE and control mice. Conclusion: These results underscore antitumor properties of Arteether that may aid in development of more effective antitumor agents.
Kayhan T Nouri-Aria
Volume 5, Issue 1 , March 2008, , Pages 1-24
Abstract
The efficacy of allergen immunotherapy for the treatment of allergic rhinoconjunctivitis with or without seasonal bronchial asthma and anaphylaxis caused by the sting of the hymenoptera class of insects has been clearly demonstrated in numerous well-designed, placebo-controlled trials. Immunotherapy ...
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The efficacy of allergen immunotherapy for the treatment of allergic rhinoconjunctivitis with or without seasonal bronchial asthma and anaphylaxis caused by the sting of the hymenoptera class of insects has been clearly demonstrated in numerous well-designed, placebo-controlled trials. Immunotherapy whether by subcutaneous injection of allergen extract or by oral/sublingual routes modifies peripheral and mucosal TH2 responses in favour of TH1 responses and augments IL-10 synthesis by TRegs both locally and by pe-ripheral T cells. Recent researches into the cellular and molecular basis of allergic reac-tions have advanced our understanding of the mechanisms involved in allergic diseases. They have also helped the development of innovative approaches that are likely to fur-ther improve the control of allergic responses in the future. Novel approaches to immu-notherapy that are currently being explored include the use of peptide-based allergen preparations, which do not bind IgE and therefore do not activate mast cells, but reduce both TH1 and TH2-cytokine synthesis, while increasing levels of IL-10. Alternative strategies include the use of adjuvants, such as nucleotide immunostimulatory se-quences derived from bacteria CpG or monophosphoryl lipid A that potentiate TH1 re-sponses. Blocking the effects of IgE using anti-IgE such as omalizumab, a recombinant humanized monoclonal antibody that selectively binds to IgE, has been shown to be a useful strategy in the treatment of allergic asthma and rhinitis. The combination of anti-IgE-monoclonal antibody omalizumab with allergen immunotherapy has proved benefi-cial for the treatment of allergic diseases, offering improved efficacy, limited adverse effects, and potential immune-modifying effects. This combination may also accelerate the rapidity by which immunotherapy induces TReg cells. If allergic diseases are due to a lack of allergen-specific TReg cells, then effective therapies should target the induction and the development of TReg cells producing cytokines such as IL-10.
Masoumeh Khamisabadi; Samaneh Arab; Masoumeh Motamedi; Nematollah khansari; Seied Mohammad Moazzeni; Zahra Gheflati; Jamshid Hadjati
Volume 5, Issue 1 , March 2008, , Pages 36-44
Abstract
Background: The use of dendritic cells (DCs) as a cellular adjuvant provides a promis-ing approach in immunotherapy of cancer. It has been demonstrated that Listeria mono-cytogenes activated DCs pulsed ex vivo with tumor antigens trigger a systemic Th1-biased specific immune response and a single dose ...
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Background: The use of dendritic cells (DCs) as a cellular adjuvant provides a promis-ing approach in immunotherapy of cancer. It has been demonstrated that Listeria mono-cytogenes activated DCs pulsed ex vivo with tumor antigens trigger a systemic Th1-biased specific immune response and a single dose of this vaccine will cause a consider-able anti tumor immunity. Objective: The present study was designed to evaluate the ability of multiple doses of tumor antigen-pulsed DCs, matured in the presence of Lis-teria monocytogenes components in induction of a potent anti-tumor response and the prevention of tumor formation in an experimental model. Methods: Bone-marrow de-rived DCs (BMDCs) were cultured in the presence of GM-CSF and IL-4. After 5 days, tumor lysates with/without Listeria monocytogenes lysate were added to the culture media for another 2 days. Mice received mature and tumor antigen pulsed dendritic cells subcutaneously in 3 groups. Tumor growth was monitored and two weeks after immu-notherapy, cytotoxic activity of CD8+ T cells was evaluated in different groups. Re-sults: According to the findings, repeated doses of vaccine did not lead to a significant increase in the activity of cytotoxic T cells and decreased tumor growth of immunized animals. Conclusion: The current study suggests that increased doses of vaccine do not have sufficient efficiency for prevention of tumor induction. Generation of T regulatory responses upon repeated doses of such vaccines should be considered in future investi-gations.
Ahmad Jalili
Volume 4, Issue 3 , December 2007, , Pages 127-144
Abstract
Dendritic cells (DCs) are antigen presenting cells with unique capability to take up and process antigens in the peripheral blood and tissues. They subsequently migrate to draining lymph nodes where they present these antigens and stimulate naive T lympho-cytes. During their life cycle, DCs go through ...
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Dendritic cells (DCs) are antigen presenting cells with unique capability to take up and process antigens in the peripheral blood and tissues. They subsequently migrate to draining lymph nodes where they present these antigens and stimulate naive T lympho-cytes. During their life cycle, DCs go through two maturation stages and are referred to as immature and mature cells, respectively. While immature DCs are very good at cap-turing antigens, mature DCs are suitably equipped to present antigens to T cells and to initiate an immune response. DCs with different phenotypes serve as sentinels in nearly all tissues including the peripheral blood, where they are continuously exposed to anti-gens. Very small numbers of activated DCs are extremely efficient at generating im-mune response against viruses, other pathogens and in experimental models of tumors. Protection against infectious microorganisms and probably against tumors is provided by complex interactions of the innate and adaptive immune systems. For the initiation to occur, pathogens must first be recognized as a “danger”. DC possesses specific recep-tors to detect such danger signals. The unique immune-stimulating properties of DC and the feasibility of manipulating their function arouse much enthusiasm and hold great promise for the treatment of cancer. Early clinical trials showed that DC can induce immune responses in cancer patients. Nonetheless, cancer treatments based on DC ad-ministration require further studies that will optimize this promising treatment modality.
Samaneh Arab; Masoumeh Motamedi; Nematollah Khansari; Seied Mohammad Moazzeni; Zahra Gheflati; Jamshid Hadjati
Volume 3, Issue 3 , September 2006, , Pages 99-105
Abstract
Background: Bacterial DNA has immunostimulatory effects on different types of immune cells such as dendritic cells (DCs). Application of DCs as a cellular adjuvant represents a promising approach in the immunotherapy of infectious disease and cancers. Objectives: To investigate the effect of tumor antigen ...
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Background: Bacterial DNA has immunostimulatory effects on different types of immune cells such as dendritic cells (DCs). Application of DCs as a cellular adjuvant represents a promising approach in the immunotherapy of infectious disease and cancers. Objectives: To investigate the effect of tumor antigen pulsed DCs in the presence of CpG-1826 in treatment of a murine model of cancer. Methods: WEHI-164 cells (Balb/c derived fibrosarcoma cell line) were injected subcutaneously in the right flank of mice. Bone marrow cells were cultured in the presence of GM-CSF and IL- 4. After 5 days, tumor lysate, CpG-1826, and oligodeoxynucleosides, as control, were added to the culture media and incubated for 2 days. Cytokine production in DCs culture media was measured by ELISA. Then DCs were injected subcutaneously around the tumor site in the right flank of mice. Tumor growth rate was monitored in case and control groups. Two weeks after DCs immunotherapy, cytotoxic assay was conducted using various amounts of effector (splenic T cells) and target cells (WEHI-164 or CT26) for 6 h. Results: Immunotherapy with DCs treated with CpG led to a significant increase in the activity of cytotoxic T cells and decreased tumor growth in immunized mice. In the control group which received DCs without CpG treatment, no change in cytotoxic activity and tumor growth rate was detected. Conclusion: The current study suggests that specific anti tumor immune responses can be induced by DCs matured with CpG and proposes CpG usage in DCs targeted clinical strategies.