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Poudel K, Ji Z, Njauw CN, Rajadurai A, Bhayana B, Sullivan RJ, Kim JO, Tsao H. Fabrication and functional validation of a hybrid biomimetic nanovaccine (HBNV) against Kit K641E -mutant melanoma. Bioact Mater 2025; 46:347-364. [PMID: 39834347 PMCID: PMC11742834 DOI: 10.1016/j.bioactmat.2024.12.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 12/03/2024] [Accepted: 12/20/2024] [Indexed: 01/22/2025] Open
Abstract
Cancer nanovaccines hold the promise for personalization, precision, and pliability by integrating all the elements essential for effective immune stimulation. An effective immune response requires communication and interplay between antigen-presenting cells (APCs), tumor cells, and immune cells to stimulate, extend, and differentiate antigen-specific and non-specific anti-tumor immune cells. The versatility of nanomedicine can be adapted to deliver both immunoadjuvant payloads and antigens from the key players in immunity (i.e., APCs and tumor cells). The imperative for novel cancer medicine is particularly pressing for less common but more devastating KIT-mutated acral and mucosal melanomas that are resistant to small molecule c-kit and immune checkpoint inhibitors. To overcome this challenge, we successfully engineered nanotechnology-enabled hybrid biomimetic nanovaccine (HBNV) comprised of membrane proteins (antigens to activate immunity and homing/targeting ligand to tumor microenvironment (TME) and lymphoid organs) from fused cells (of APCs and tumor cells) and immunoadjuvant. These HBNVs are efficiently internalized to the target cells, assisted in the maturation of APCs via antigens and adjuvant, activated the release of anti-tumor cytokines/inhibited the release of immunosuppressive cytokine, showed a homotypic effect on TME and lymph nodes, activated the anti-tumor immune cells/downregulated the immunosuppressive immune cells, reprogram the tumor microenvironment, and showed successful anti-tumor therapeutic and prophylactic effects.
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Affiliation(s)
- Kishwor Poudel
- Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Zhenyu Ji
- Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Ching-Ni Njauw
- Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Anpuchchelvi Rajadurai
- Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Brijesh Bhayana
- Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Ryan J. Sullivan
- Mass General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jong Oh Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Hensin Tsao
- Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Mass General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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Cai M, Fu T, Zhu R, Hu P, Kong J, Liao S, Du Y, Zhang Y, Qu C, Dong X, Yin X, Ni J. An iron-based metal-organic framework nanoplatform for enhanced ferroptosis and oridonin delivery as a comprehensive antitumor strategy. Acta Pharm Sin B 2024; 14:4073-4086. [PMID: 39309488 PMCID: PMC11413704 DOI: 10.1016/j.apsb.2024.05.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 04/30/2024] [Accepted: 05/07/2024] [Indexed: 09/25/2024] Open
Abstract
Ferroptosis is a recently discovered pathway for regulated cell death pathway. However, its efficacy is affected by limited iron content and intracellular ion homeostasis. Here, we designed a metal-organic framework (MOF)-based nanoplatform that incorporates calcium peroxide (CaO2) and oridonin (ORI). This platform can improve the tumor microenvironment and disrupt intracellular iron homeostasis, thereby enhancing ferroptosis therapy. Fused cell membranes (FM) were used to modify nanoparticles (ORI@CaO2@Fe-TCPP, NPs) to produce FM@ORI@CaO2@Fe-TCPP (FM@NPs). The encapsulated ORI inhibited the HSPB1/PCBP1/IREB2 and FSP1/COQ10 pathways simultaneously, working in tandem with Fe3+ to induce ferroptosis. Photodynamic therapy (PDT) guided by porphyrin (TCPP) significantly enhanced ferroptosis through excessive accumulation of reactive oxygen species (ROS). This self-amplifying strategy promoted robust ferroptosis, which could work synergistically with FM-mediated immunotherapy. In vivo experiments showed that FM@NPs inhibited 91.57% of melanoma cells within six days, a rate 5.6 times higher than chemotherapy alone. FM@NPs were biodegraded and directly eliminated in the urine or faeces without substantial toxicity. Thus, this study demonstrated that combining immunotherapy with efficient ferroptosis induction through nanotechnology is a feasible and promising strategy for melanoma treatment.
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Affiliation(s)
- Mengru Cai
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Tingting Fu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Rongyue Zhu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Panxiang Hu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Jiahui Kong
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Shilang Liao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Yuji Du
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Yongqiang Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Changhai Qu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Xiaoxv Dong
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Xingbin Yin
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Jian Ni
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
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Wang D, Xue M, Chen J, Chen H, Liu J, Li Q, Xie Y, Hu Y, Ni Y, Zhou Q. Macrophage-derived implantable vaccine prevents postsurgical tumor recurrence. Biomaterials 2021; 278:121161. [PMID: 34601198 DOI: 10.1016/j.biomaterials.2021.121161] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 09/22/2021] [Accepted: 09/27/2021] [Indexed: 02/07/2023]
Abstract
Immunotherapy emerges as a potential therapeutic strategy against tumor relapse. However, immunosuppressive tumor microenvironment poses an obstacle to immunotherapy. Of particular note is that macrophages are abundant in solid tumors and tumor-associated macrophages (TAMs) are mainly anti-inflammatory and protumoral. Therefore, re-educating TAMs will be critical for improving the antitumor efficacy of immunotherapy. Herein we engineered a macrophage-derived implantable vaccine for suppressing postsurgical tumor relapse. The vaccine comprised hybrid cytomembranes from macrophages/tumor cells and an immunoadjuvant, cytosinephosphate-guanosine oligodeoxynucleotides (CpG ODNs). The vaccine was further embedded into a calcium alginate hydrogel for tissue-localized delivery. Results show that the vaccine could induce the shift from anti-inflammatory M2-like TAMs to proinflammatory M1-like macrophage. Moreover, the vaccine stimulated systemic immunity by facilitating dendritic cells (DCs) maturation and memory T (T EM) cell activation, forming a self-replenishing circulation in tumor microenvironment. Consequently, the vaccine could prevent the postsurgical tumor relapse at both the primary and distant tumor sites. In addition, the lung metastasis was also reduced by the vaccine implantation in mice. The multifunctional vaccine prepared from biomacromolecule and nature-derived material provides a biocompatible and versatile tool for re-educating TAMs and preventing postsurgical tumor recurrence.
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Affiliation(s)
- Dongqing Wang
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing, 400016, China
| | - Mingming Xue
- Basic Medical College, Office of Academic Affairs, Inner Mongolia Medical University, Jinshan Avenue, Jinshan Development Zone, Hohhot, 010030, PR China
| | - Jun Chen
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics and University of Chinese Academy of Sciences (UCAS), Chinese Academy of Sciences (CAS), Beijing, 100049, PR China
| | - Heying Chen
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing, 400016, China
| | - Jiahe Liu
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing, 400016, China
| | - Qianyin Li
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing, 400016, China
| | - Yajun Xie
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing, 400016, China
| | - Yi Hu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics and University of Chinese Academy of Sciences (UCAS), Chinese Academy of Sciences (CAS), Beijing, 100049, PR China.
| | - Yilu Ni
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing, 400016, China.
| | - Qin Zhou
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing, 400016, China.
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Sun X, Wu B, Geng L, Zhang J, Qin G. Xiaokang Liuwei Dihuang decoction ameliorates the immune infertility of male rats induced by lipopolysaccharide through regulating the levels of sex hormones, reactive oxygen species, pro-apoptotic and immune factors. Biomed Pharmacother 2021; 139:111514. [DOI: 10.1016/j.biopha.2021.111514] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 03/11/2021] [Accepted: 03/14/2021] [Indexed: 12/16/2022] Open
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Role of targeted immunotherapy for pancreatic ductal adenocarcinoma (PDAC) treatment: An overview. Int Immunopharmacol 2021; 95:107508. [PMID: 33725635 DOI: 10.1016/j.intimp.2021.107508] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/18/2021] [Accepted: 02/12/2021] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid tumors with a high mortality rate and poor survival rate. Depending on the tumor stage, PDAC is either treated by resection surgery, chemotherapies, or radiotherapies. Various chemotherapeutic agents have been used to treat PDAC, alone or in combination. Despite the combinations, chemotherapy exhibits many side-effects leading to an increase in the toxicity profile amongst the PDAC patients. Additionally, these standard chemotherapeutic agents have only a modest impact on patient survival due to their limited efficacy. PDAC was previously considered as an immunologically silent malignancy, but recent findings have demonstrated that effective immune-mediated tumor cell death can be used for its treatment. PDAC is characterized by an immunosuppressive tumor microenvironment accompanied by the major expression of myeloid-derived suppressor cells (MDSC) and M2 tumor-associated macrophages. In contrast, the expression of CD8+ T cells is significantly low. Additionally, infiltration of mast cells in PDAC correlates with the poor prognosis. Immunotherapeutic agents target the immunity mediators and empower them to suppress the tumor and effectively treat PDAC. Different targets are studied and exploited to induce an antitumor immune response in PDAC patients. In recent times, site-specific delivery of immunotherapeutics also gained attention among researchers to effectively treat PDAC. In the present review, existing immunotherapies for PDAC treatment along with their limitations are addressed in detail. The review also includes the pathophysiology, traditional strategies and significance of targeted immunotherapies to combat PDAC effectively. Separately, the identification of ideal targets for the targeted therapy of PDAC is also reviewed exhaustively. Additionally, the review also addresses the applications of targeted immunotherapeutics like checkpoint inhibitors, adoptive T-cell therapy etc.
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Liu WL, Zou MZ, Liu T, Zeng JY, Li X, Yu WY, Li CX, Ye JJ, Song W, Feng J, Zhang XZ. Cytomembrane nanovaccines show therapeutic effects by mimicking tumor cells and antigen presenting cells. Nat Commun 2019; 10:3199. [PMID: 31324770 PMCID: PMC6642123 DOI: 10.1038/s41467-019-11157-1] [Citation(s) in RCA: 186] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 06/26/2019] [Indexed: 01/08/2023] Open
Abstract
Most cancer vaccines are unsuccessful in eliciting clinically relevant effects. Without using exogenous antigens and adoptive cells, we show a concept of utilizing biologically reprogrammed cytomembranes of the fused cells (FCs) derived from dendritic cells (DCs) and cancer cells as tumor vaccines. The fusion of immunologically interrelated two types of cells results in strong expression of the whole tumor antigen complexes and the immunological co-stimulatory molecules on cytomembranes (FMs), allowing the nanoparticle-supported FM (NP@FM) to function like antigen presenting cells (APCs) for T cell immunoactivation. Moreover, tumor-antigen bearing NP@FM can be bio-recognized by DCs to induce DC-mediated T cell immunoactivation. The combination of these two immunoactivation pathways offers powerful antitumor immunoresponse. Through mimicking both APCs and cancer cells, this cytomembrane vaccine strategy can develop various vaccines toward multiple tumor types and provide chances for accommodating diverse functions originating from the supporters.
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Affiliation(s)
- Wen-Long Liu
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P.R. China
| | - Mei-Zhen Zou
- The Institute for Advanced Studies, Wuhan University, Wuhan, 430072, P.R. China
| | - Tao Liu
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P.R. China
| | - Jin-Yue Zeng
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P.R. China
| | - Xue Li
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P.R. China
| | - Wu-Yang Yu
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P.R. China
| | - Chu-Xin Li
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P.R. China
| | - Jing-Jie Ye
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P.R. China
| | - Wen Song
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P.R. China
| | - Jun Feng
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P.R. China.
| | - Xian-Zheng Zhang
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P.R. China. .,The Institute for Advanced Studies, Wuhan University, Wuhan, 430072, P.R. China.
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Ito Z, Kan S, Bito T, Horiuchi S, Akasu T, Yoshida S, Kajihara M, Hokari A, Saruta M, Yoshida N, Kobayashi M, Ohkusa T, Shimodaira S, Okamoto M, Sugiyama H, Koido S. Predicted Markers of Overall Survival in Pancreatic Cancer Patients Receiving Dendritic Cell Vaccinations Targeting WT1. Oncology 2019; 97:135-148. [DOI: 10.1159/000500359] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Accepted: 04/15/2019] [Indexed: 11/19/2022]
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Liu WL, Zou MZ, Liu T, Zeng JY, Li X, Yu WY, Li CX, Ye JJ, Song W, Feng J, Zhang XZ. Expandable Immunotherapeutic Nanoplatforms Engineered from Cytomembranes of Hybrid Cells Derived from Cancer and Dendritic Cells. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2019; 31:e1900499. [PMID: 30907473 DOI: 10.1002/adma.201900499] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 03/07/2019] [Indexed: 05/18/2023]
Abstract
Using the cytomembranes (FMs) of hybrid cells acquired from the fusion of cancer and dendritic cells (DCs), this study offers a biologically derived platform for the combination of immunotherapy and traditional oncotherapy approaches. Due to the immunoactivation implicated in the cellular fusion, FMs can effectively express whole cancer antigens and immunological co-stimulatory molecules for robust immunotherapy. FMs share the tumor's self-targeting character with the parent cancer cells. In bilateral tumor-bearing mouse models, the FM-coated nanophotosensitizer causes durable immunoresponse to inhibit the rebound of primary tumors post-nanophotosensitizer-induced photodynamic therapy (PDT). The FM-induced immunotherapy displays ultrahigh antitumor effects even comparable to that of PDT. On the other hand, PDT toward primary tumors enhances the immunotherapy-caused regression of the irradiation-free distant tumors. Consequently, both the primary and the distant tumors are almost completely eliminated. This tumor-specific immunotherapy-based nanoplatform is potentially expandable to multiple tumor types and readily equipped with diverse functions owing to the flexible nanoparticle options.
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Affiliation(s)
- Wen-Long Liu
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Mei-Zhen Zou
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
- The Institute for Advanced Studies, Wuhan University, Wuhan, 430072, P. R. China
| | - Tao Liu
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Jin-Yue Zeng
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Xue Li
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Wu-Yang Yu
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Chu-Xin Li
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Jing-Jie Ye
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Wen Song
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Jun Feng
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
| | - Xian-Zheng Zhang
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, 430072, P. R. China
- The Institute for Advanced Studies, Wuhan University, Wuhan, 430072, P. R. China
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Koido S. Dendritic-Tumor Fusion Cell-Based Cancer Vaccines. Int J Mol Sci 2016; 17:ijms17060828. [PMID: 27240347 PMCID: PMC4926362 DOI: 10.3390/ijms17060828] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Revised: 05/19/2016] [Accepted: 05/23/2016] [Indexed: 12/20/2022] Open
Abstract
Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that play a critical role in the induction of antitumor immunity. Therefore, various strategies have been developed to deliver tumor-associated antigens (TAAs) to DCs as cancer vaccines. The fusion of DCs and whole tumor cells to generate DC-tumor fusion cells (DC-tumor FCs) is an alternative strategy to treat cancer patients. The cell fusion method allows DCs to be exposed to the broad array of TAAs originally expressed by whole tumor cells. DCs then process TAAs endogenously and present them through major histocompatibility complex (MHC) class I and II pathways in the context of costimulatory molecules, resulting in simultaneous activation of both CD4⁺ and CD8⁺ T cells. DC-tumor FCs require optimized enhanced immunogenicity of both DCs and whole tumor cells. In this context, an effective fusion strategy also needs to produce immunogenic DC-tumor FCs. We discuss the potential ability of DC-tumor FCs and the recent progress in improving clinical outcomes by DC-tumor FC-based cancer vaccines.
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Affiliation(s)
- Shigeo Koido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 277-8567 Chiba, Japan.
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Kajihara M, Takakura K, Kanai T, Ito Z, Matsumoto Y, Shimodaira S, Okamoto M, Ohkusa T, Koido S. Advances in inducing adaptive immunity using cell-based cancer vaccines: Clinical applications in pancreatic cancer. World J Gastroenterol 2016; 22:4446-58. [PMID: 27182156 PMCID: PMC4858628 DOI: 10.3748/wjg.v22.i18.4446] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 04/01/2016] [Accepted: 04/15/2016] [Indexed: 02/06/2023] Open
Abstract
The incidence of pancreatic ductal adenocarcinoma (PDA) is on the rise, and the prognosis is extremely poor because PDA is highly aggressive and notoriously difficult to treat. Although gemcitabine- or 5-fluorouracil-based chemotherapy is typically offered as a standard of care, most patients do not survive longer than 1 year. Therefore, the development of alternative therapeutic approaches for patients with PDA is imperative. As PDA cells express numerous tumor-associated antigens that are suitable vaccine targets, one promising treatment approach is cancer vaccines. During the last few decades, cell-based cancer vaccines have offered encouraging results in preclinical studies. Cell-based cancer vaccines are mainly generated by presenting whole tumor cells or dendritic cells to cells of the immune system. In particular, several clinical trials have explored cell-based cancer vaccines as a promising therapeutic approach for patients with PDA. Moreover, chemotherapy and cancer vaccines can synergize to result in increased efficacies in patients with PDA. In this review, we will discuss both the effect of cell-based cancer vaccines and advances in terms of future strategies of cancer vaccines for the treatment of PDA patients.
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Yu Z, Geng J, Zhang M, Zhou Y, Fan Q, Chen J. Treatment of osteosarcoma with microwave thermal ablation to induce immunogenic cell death. Oncotarget 2015; 5:6526-39. [PMID: 25153727 PMCID: PMC4171648 DOI: 10.18632/oncotarget.2310] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Microwave ablation (MWA) has been used as a classical hyperthermic ablation method for decades with the intention to induce direct killing of tumor cells or modulation of tumor architecture. The purpose of this study was to explore whether MWA induced tumor cell death could generate an immunogenic source of tumor antigens and elicit tumor-specific immune responses, taking an alternative antitumor effects. Three kinds of osteosarcoma cell lines, respectively derived from mice, rats and human, were selected as ablation models. In vitro and in situ tumor ablation were both performed to detect the “damage-associated molecular patterns” (DAMPs) exposure level. Active ablated products vaccination resulted in complete protection in both mouse and rat tumor-bearing models, which was mediated primarily by vaccine-elicited CD8+ T cells. These effector cells functioned by releasing IFN-γ and TNF-α in the presence of target cells, which may trigger FasL-directed cell apoptosis. These data suggest that MWA-processed osteosarcoma cells could be applied to generate specific antitumor effects, especially for in situ ablation. Hence, MWA could be used in combination with immunotherapy, especially for patients who have failed chemotherapy or who have limited treatment options.
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Affiliation(s)
- Zhe Yu
- Center of Orthopedic Surgery, Orthopedics Oncology Institute of Chinese PLA, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, P. R. China; These authors contributed equally to this work
| | - Jie Geng
- Medical Department of Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, P. R. China; These authors contributed equally to this work
| | - Minghua Zhang
- Center of Orthopedic Surgery, Orthopedics Oncology Institute of Chinese PLA, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, P. R. China
| | - Yong Zhou
- Center of Orthopedic Surgery, Orthopedics Oncology Institute of Chinese PLA, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, P. R. China
| | - Qingyu Fan
- Center of Orthopedic Surgery, Orthopedics Oncology Institute of Chinese PLA, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, P. R. China
| | - Jingyuan Chen
- Faculty of Military Preventive Medicine, Fourth Military Medical University, Xi'an, Shaanxi P. R. China
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12
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Kajihara M, Takakura K, Ohkusa T, Koido S. The impact of dendritic cell-tumor fusion cells on cancer vaccines - past progress and future strategies. Immunotherapy 2015; 7:1111-22. [PMID: 26507578 DOI: 10.2217/imt.15.73] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Dendritic cells (DCs) are potent antigen-presenting cells that can be used in cancer vaccines. Thus, various strategies have been developed to deliver tumor-associated antigens via DCs. One strategy includes administering DC-tumor fusion cells (DC-tumor FCs) to induce antitumor immune responses in cancer patients. However, clinical trials using this strategy have fallen short of expectations. Several factors might limit the efficacy of these anticancer vaccines. To induce efficient antitumor immune responses and enhance potential clinical benefits, DC-tumor FC-based cancer vaccines require manipulations that improve immunogenicity for both DCs and whole tumor cells. This review addresses recent progress in improving clinical outcomes using DC-tumor FC-based cancer vaccines.
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Affiliation(s)
- Mikio Kajihara
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kazuki Takakura
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Toshifumi Ohkusa
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Shigeo Koido
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
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13
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Johnson S, Duncan J, Hussain SA, Chen G, Luo J, Mclaurin C, May W, Rajkowska G, Ou XM, Stockmeier CA, Wang JM. The IFNγ-PKR pathway in the prefrontal cortex reactions to chronic excessive alcohol use. Alcohol Clin Exp Res 2015; 39:476-84. [PMID: 25704249 DOI: 10.1111/acer.12650] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 12/01/2014] [Indexed: 11/29/2022]
Abstract
BACKGROUND Brain cell death is a major pathological consequence of alcohol neurotoxicity. However, the molecular cascades in alcohol-induced brain tissue injury are unclear. METHODS Using Western blot and double immunofluorescence, we examined the expression of interferon (IFN)-induced protein kinase R (PKR), phosphorylated-PKR (p-PKR), and IFN gamma (IFNγ) in the prefrontal cortex (PFC) of postmortem brains from subjects with alcohol use disorders (AUD). RESULTS The protein levels of PKR, p-PKR, and IFNγ were significantly increased in subjects with AUD compared with control subjects without AUD, and a younger age of onset of AUD was significantly correlated with higher protein levels of p-PKR. In addition, elevated PKR- and p-PKR-IR were observed in both neurons and astrocytes in the PFC of subjects with AUD compared to subjects without AUD. CONCLUSIONS The activation of the IFNγ-PKR pathway in PFC of humans is associated with chronic excessive ethanol use with an age of onset dependent manner, and activation of this pathway may play a pivotal role in AUD-related brain tissue injury. This study provides insight into neurodegenerative key factors related to AUD and identifies potential targets for the treatment of alcohol-induced neurotoxicity.
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Affiliation(s)
- Shakevia Johnson
- Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, Mississippi
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Abstract
We have developed cell fusion vaccines generated with dendritic cells (DCs) and whole tumor cells to induce antigen-specific antitumor immunity. This approach allows DCs to be exposed to the entire repertoire of tumor-associated antigens (TAAs) originally expressed by the tumor cell, to process them endogenously, and to present antigenic epitopes thought the MHC class I and class II pathways to activate both CD8+ and CD4+ T cells, respectively. The therapeutic efficacy of DC/tumor fusion cell vaccines requires the improved immunogenicity of both cells. Here, we describe the strategy to generate DC/tumor fusion cells.
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Affiliation(s)
- Shigeo Koido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8564, Japan,
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15
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Chen Y, Lei Y, Huang Y, Rao Z, Ye L, Zhao G, Wang X. [Accumulation-associated protein gene and TGF-beta 1 affects the formation of lung cancer-related biological material Staphylococcus epidermidis biofilm]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2014; 17:308-14. [PMID: 24758905 PMCID: PMC6000014 DOI: 10.3779/j.issn.1009-3419.2014.04.04] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
背景与目的 研究聚集相关蛋白（accumulation-associated protein, Aap）基因及转化生长因子β1（TGF-β1）对肺癌相关生物材料表皮葡萄球菌（SE）生物膜形成的影响。 方法 种属鉴定分离临床肺癌患者植入材料感染表皮葡萄球菌株，PCR法检测生物膜形成相关基因Aap，检测表皮葡萄球菌Aap基因株生物形成能力。密度梯度法提取非小细胞肺癌患者外周血单个核细胞，与人肺腺癌细胞A549在不同浓度（10 ng/mL, 20 ng/mL, 40 ng/mL）TGF-β1共培养30 h后，取上清液分别加入SE Aap+株、SE Aap-株下与医用硅橡胶培养30 h，半定量粘附试验测各组细菌生物膜形成的情况，扫描电镜观察材料表面生物膜微观情况。 结果 Aap基因的与表皮葡萄球菌生物膜的形成密切相关（P < 0.01）。在（10 ng/mL, 20 ng/mL, 40 ng/mL）TGF-β1浓度组医用硅橡胶表面SE Aap+生物膜的厚度大于空白组（P < 0.01）。SE Aap+株在TGF-β1浓度组间生物膜的厚度无明显差异（P > 0.05）。在不同浓度TGF-β1因子刺激下SE Aap-株均不能形成明显细菌生物膜。 结论 在肺癌患者植入材料引起感染中表皮葡萄球菌Aap基因表达阳性株较易形成细菌生物膜，TGF-β1对SE Aap阳性形成细菌生物膜有一定促进作用。
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Affiliation(s)
- Ying Chen
- Deparment of Thoracic Surgery, the Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming 650118, China
| | - Yujie Lei
- Deparment of Thoracic Surgery, the Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming 650118, China
| | - Yunchao Huang
- Deparment of Thoracic Surgery, the Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming 650118, China
| | - Zhongming Rao
- Deparment of Thoracic Surgery, the Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming 650118, China
| | - Lianhua Ye
- Deparment of Thoracic Surgery, the Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming 650118, China
| | - Guangqiang Zhao
- Deparment of Thoracic Surgery, the Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming 650118, China
| | - Xiaoyan Wang
- Deparment of Cardiovascular Surgery, the Affiliated Yan'an Hospital of Kunming Medical University,
Kunming 650051, China
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Koido S, Homma S, Okamoto M, Namiki Y, Takakura K, Uchiyama K, Kajihara M, Arihiro S, Imazu H, Arakawa H, Kan S, Komita H, Kamata Y, Ito M, Ohkusa T, Gong J, Tajiri H. Strategies to improve the immunogenicity of anticancer vaccines based on dendritic cell/malignant cell fusions. Oncoimmunology 2013; 2:e25994. [PMID: 24228229 PMCID: PMC3820816 DOI: 10.4161/onci.25994] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2013] [Accepted: 07/31/2013] [Indexed: 02/06/2023] Open
Abstract
The rationale for fusing dendritic cells (DCs) with whole tumor cells to generate anticancer vaccines resides in the fact that the former operate as potent antigen-presenting cells, whereas the latter express a constellation of tumor-associated antigens (TAAs). Although the administration of DC/malignant cell fusions to cancer patients is safe and this immunotherapeutic intervention triggers efficient tumor-specific T-cell responses in vitro, a limited number of objective clinical responses to DC/cancer cell fusions has been reported thus far. This review discusses novel approaches to improve the immunogenicity of DC/malignant cell fusions as anticancer vaccines.
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Affiliation(s)
- Shigeo Koido
- Division of Gastroenterology and Hepatology; Department of Internal Medicine; The Jikei University School of Medicine; Tokyo, Japan ; Institute of Clinical Medicine and Research; The Jikei University School of Medicine; Tokyo, Japan ; Department of Oncology; Institute of DNA Medicine; The Jikei University School of Medicine; Tokyo, Japan
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Koido S, Homma S, Okamoto M, Namiki Y, Kan S, Takakura K, Kajihara M, Uchiyama K, Hara E, Ohkusa T, Gong J, Tajiri H. Improved immunogenicity of fusions between ethanol-treated cancer cells and dendritic cells exposed to dual TLR stimulation. Oncoimmunology 2013; 2:e25375. [PMID: 24167764 PMCID: PMC3805650 DOI: 10.4161/onci.25375] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2013] [Accepted: 06/12/2013] [Indexed: 11/26/2022] Open
Abstract
Tumor-derived transforming growth factor β1 (TGFβ1) generally abrogates the immunogenicity of dendritic cells (DCs) fused to whole cancer cells. We have recently revealed that ethanol-treated neoplastic cells fused to DCs exposed to 2 Toll-like receptor agonists efficiently induce cytotoxic T lymphocytes via TGFβ1 blockade and the production of interleukin-12.
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Affiliation(s)
- Shigeo Koido
- Division of Gastroenterology and Hepatology; Department of Internal Medicine; The Jikei University School of Medicine; Tokyo, Japan ; Institute of Clinical Medicine and Research; The Jikei University School of Medicine; Tokyo, Japan ; Department of Oncology; Institute of DNA Medicine; The Jikei University School of Medicine; Tokyo, Japan
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