Journal Articles

Cellular immunotherapy

Treatment approaches with dendritic cells, cytokine-induced killer cells, natural killer cells, etc. or hematopoietic stem cell transplantation

Combination therapy improves immune response and prognosis in patients with advanced oral mucosal melanoma: A clinical treatment success

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OBJECTIVE: This study was undertaken to analyze disease response and immune response to assess treatment effectiveness and success in patients with advanced oral mucosal melanoma treated with cytokines injection, cryosurgery, and adoptive cell transfer therapy. STUDY DESIGN: Ten patients were enrolled in the study, and the relevant characteristics and immunologic differences were evaluated. RESULTS: All patients achieved an objective clinical response according to the Response Evaluation Criteria in Solid Tumors, including 7 cases of continuing complete remission (55, 27, 87 + , 58(+), 58 + , 45 + , and 37 + months) and 3 cases of partial remission (30, 12, and 9 months). Five responders are currently alive. After combination therapy, we observed that the proportion of CD3+ lymphocytes and the secretion of interferon-gamma increased, whereas interleukin-10 decreased. In the assay of improved cytokine-induced killer cells, CD4+CD25+ regulatory T cells declined, and natural killer cells upregulated. Meanwhile, the proliferation rate of in vitro cultured improved cytokine-induced killer cells improved after courses of therapy. CONCLUSIONS: Combination therapy of cytokine injection, cryosurgery, and transfer of improved cytokine-induced killer cells may be a promising approach for patients with oral mucosal melanoma.

Author Info: (1) Department of Oral and Maxillofacial Surgery, Clinical Laboratory, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology

Author Info: (1) Department of Oral and Maxillofacial Surgery, Clinical Laboratory, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China. (2) Department of Oral and Maxillofacial Surgery, Clinical Laboratory, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China. (3) Department of Oral and Maxillofacial Surgery, Clinical Laboratory, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China. (4) Department of Oral and Maxillofacial Surgery, Clinical Laboratory, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China. (5) Department of Oral and Maxillofacial Surgery, Clinical Laboratory, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China. Electronic address: Wanghua9@mail.sysu.edu.cn.

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Strategies to enhance NK cell function for the treatment of tumors and infections

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Natural killer (NK) cells are innate immune cells equipped with the ability to rapidly kill stressed cells that are neoplastic or virally infected. These cells are especially important in settings where these stressed cells downregulate MHC class I molecules and evade recognition by cytotoxic T cells. However, the activity of NK cells alone is often suboptimal to fully control tumor growth or to clear viral infections. Thus, the enhancement of NK cell function is necessary to fully harness their antitumor or antiviral potential. In this review, we discuss how NK cell function can be augmented by the modulation of signal transduction pathways, by the manipulation of inhibitory/activating receptors on NK cells, and by cytokine-induced activation. We also discuss how some of these strategies are currently impacting NK cells in the treatment of cancer and infections.

Author Info: (1) Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. (2) Department of Pathology and Laboratory Medicine, Perelman

Author Info: (1) Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. (2) Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. (3) Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.

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Carfilzomib combined with ex vivo-expanded patient autologous natural killer cells for myeloma immunotherapy

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Natural killer (NK) cell-based immunotherapy is promising, as NK cells are in the first line of defense against cancer and capital of lysing tumor cells without pre-stimulation. However, NK cells from multiple myeloma (MM) patients are always deficient in numbers and the expression of certain activating receptors, disabling them in cytotoxicity against the cancer. Therefore, effective strategies to expand NK cells and increase NK cell-mediated cytotoxicity against MM are significant. Here, NK cells were efficiently expanded from peripheral blood mononuclear cells (PBMCs) of newly diagnosed MM patients after co-culture with irradiated K562 cells transfected with 41BBL and membrane-bound interleukin (IL)-15 (K562-mb15-41BBL) in the presence of 200 IU/ml human IL-2. The ex vivo-expanded NK cells were demonstrated to vigorously kill both MM cells and autologous primary MM cells without significant lysis of patient normal cells. Further exploration revealed a significant increase in cell surface expression of most activating receptors of NK cells and indicated that expanded NK (exp-NK) cell killing of MM cells was mediated by perforin/granzyme. NK cells are capital of lysing human leukocyte antigen (HLA) I-deficient tumor cells and carfizomib, a selective proteasome inhibitor approved for the treatment of relapsed/refractory MM patient, down-regulates the expression of HLA class I, thus enhancing NK cell-mediated lysis in MM. Here, we found for the first time that carfizomib dramatically augmented ex vivo exp-NK cell cytotoxicity against patient autologous MM cells, suggesting the use of exp-NK alone or in combination with the drug to treat MM patient.

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11)

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11)

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Dendritic cell trafficking in tumor-bearing mice

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Prostate cancer is one of the leading causes of cancer deaths, with no curative treatments once it spreads. Alternative therapies, including immunotherapy, have shown limited efficacy. Dendritic cells (DC) have been widely used in the treatment of various malignancies. DC capture antigens and move to the lymphoid organs where they prime naive T cells. Interaction between DC and T cells are most active in lymph nodes and suppression of DC trafficking to lymph nodes impairs the immune response. In this work, we aimed to study trafficking of DC in vivo via various routes of delivery, to optimize the effectiveness of DC-based therapy. A DC labeling system was developed using 1,1'-dioctadecyltetramethyl indotricarbocyanine Iodine for in vivo fluorescent imaging. DC harvested from C57B/6 mice were matured, labeled, and injected intravenously, subcutaneously, or intratumorally, with or without antigen loading with whole tumor lysate, into C57B/6 mice inoculated with RM-1 murine prostate tumor cells. Signal intensity was measured in vivo and ex vivo. Signal intensity at the tumor site increased over time, suggesting trafficking of DC to the tumor with all modes of injection. Subcutaneous injection showed preferential trafficking to lymph nodes and tumor. Intravenous injection showed trafficking to lungs, intestines, and spleen. Subcutaneous injection of DC pulsed with whole tumor lysate resulted in the highest increase in signal intensity at the tumor site and lymph nodes, suggesting subcutaneous injection of primed DC leads to highest preferential trafficking of DC to the immunocompetent organs.

Author Info: (1) Division of Urology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. (2) Division of Urology, Virginia Commonwealth University School of Medicine, Richmond, VA

Author Info: (1) Division of Urology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. (2) Division of Urology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. (3) Division of Urology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. (4) Division of Urology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. (5) Department of Radiology, Center for Molecular Imaging, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. (6) Department of Radiology, Center for Molecular Imaging, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. (7) Department of Radiology, Center for Molecular Imaging, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. (8) Department of Radiology, Center for Molecular Imaging, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA. (9) Division of Urology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. gguruli@vcu.edu. Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA. gguruli@vcu.edu.

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Clinical efficacy and safety of CIK plus radiotherapy for lung cancer: A meta-analysis of 16 randomized controlled trials

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OBJECTIVE: Cytokine-induced killer cells (CIK) therapy is the most commonly used cellular immunotherapy. The CIK plus radiotherapy was clinically used in a wide range of treatment, but the efficacy of their combination against lung cancer is not clear yet. Therefore, we systematically evaluated all the related studies to reveal the combination's clinical efficacy and safety in lung cancer. MATERIALS AND METHODS: We collected all the studies about CIK plus radiotherapy for lung cancer in Medline, Embase, Web of Science (ISI), China National Knowledge Infrastructure Database (CNKI), Chinese Scientific Journals Full-Text Database (VIP), Wanfang Database, China Biological Medicine Database (CBM) and Cochrane Central Register of Controlled Trials (CENTRAL), Chinese clinical trial registry (Chi-CTR), WHO International Clinical Trials Registry Platform (WHO-ICTRP) and US-clinical trials (March 2017). We evaluated their bias risk according to the Cochrane evaluation handbook of randomized controlled trials (RCTs), extracted all the data, and synthesized the data using meta analysis. RESULTS: We included 16 RCTs involving 1197 patients with lung cancer, and most trials had unclear risk of bias. Meta-analysis showed that CIK therapy could increase the objective response rate (ORR) (1.32, 1.21 to 1.44), the disease control rate (DCR) (1.13, 1.04 to 1.23), the 1-year overall survival (OS) rate (1.38, 1.16 to 1.63) and the 2-year OS rate (1.23, 1.11 to 1.35). DCs-CIK cells increased the 3-year OS rate (1.66, 1.20 to 2.29). DCs-CIK therapy could increase the CD3(+)T cells (2.27, 1.47 to 3.06), CD4(+)T cells (1.28, 0.74 to 1.81), NK cells (2.04, 0.74 to 3.33) and CD4(+)/CD8(+) T cells ratio (1.20, 0.64 to 1.76) and decrease the CD8(+)T cells (-0.84, -1.60 to -0.08). CIK plus radiotherapy had lower risk of leukopenia (0.85, 0.76 to 0.95) and higher risk of fever (5.50, 2.71 to 11.17) than that of radiotherapy alone. Subgroup analysis showed that CIK plus radiotherapy, mainly three dimensional conformal radiotherapy (3D-CRT) could increase the ORR, DCR, 1- and 2- year OS rate in non-small cell lung cancer (NSCLC), and only DCR in small cell lung cancer (SCLC). Compared with CIK plus pure radiotherapy, except for the ORR, DCR, 1-year OS rate, CIK plus chemoradiotherapy could still increase the 2-year OS rate. DCs-CIK could increase the ORR, DCR, 1- and 2-year OS rate, CIK cells could only increase the ORR and the 1-year OS rate. CONCLUSIONS: CIK plus radiotherapy can improve the clinical response, OS and PFS in lung cancer. It may have low risk of leukopenia and high risk of fever. CIK plus chemoradiotherapy, mainly 3D-CRT can improve the clinical response, OS and PFS in NSCLC. DCs-CIK cells can improve the 1-, 2- and 3-year OS rate, and the 1- and 2-year PFS rate, and CIK cells only improve the 1-year OS rate. DCs-CIK cells can repair the antitumor immunity.

Author Info: (1) Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical College, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China

Author Info: (1) Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical College, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China; Department of Respiratory Medicine (Center for Evidence-Based and Translational Medicine of major infectious diseases), Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China. Electronic address: zy426f@163.com. (2) Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical College, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China; Department of Respiratory Medicine (Center for Evidence-Based and Translational Medicine of major infectious diseases), Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China. (3) Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical College, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China. (4) Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical College, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China; Department of Respiratory Medicine (Center for Evidence-Based and Translational Medicine of major infectious diseases), Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China. (5) Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical College, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China. (6) Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical College, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China; Department of Respiratory Medicine (Center for Evidence-Based and Translational Medicine of major infectious diseases), Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China. (7) Department of Immunology, Southwest Medical University, Luzhou 646000, Sichuan, China. (8) Department of Oncology, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China. Electronic address: fengjh100@163.com. (9) Department of Immunology, Zunyi Medical College, Zunyi 563000, Guizhou, China. (10) Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical College, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China; Department of Respiratory Medicine (Center for Evidence-Based and Translational Medicine of major infectious diseases), Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China. (11) Evidence-Based Medicine Center of Lanzhou University, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, Gansu, China. (12) Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical College, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China; Department of Pediatric Surgery, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China. (13) Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China. (14) Department of Immunology, Southwest Medical University, Luzhou 646000, Sichuan, China. (15) Outpatient Department of Psychological Counseling Clinic (Center for Evidence-Based and Translational Medicine of major infectious diseases), Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China.

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Gamma Delta T Cell Therapy for Cancer: It Is Good to be Local

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Human gamma delta T cells have extraordinary properties including the capacity for tumor cell killing. The major gamma delta T cell subset in human beings is designated Vgamma9Vdelta2 and is activated by intermediates of isoprenoid biosynthesis or aminobisphosphonate inhibitors of farnesyldiphosphate synthase. Activated cells are potent for killing a broad range of tumor cells and demonstrated the capacity for tumor reduction in murine xenotransplant tumor models. Translating these findings to the clinic produced promising initial results but greater potency is needed. Here, we review the literature on gamma delta T cells in cancer therapy with emphasis on the Vgamma9Vdelta2 T cell subset. Our goal was to examine obstacles preventing effective Vgamma9Vdelta2 T cell therapy and strategies for overcoming them. We focus on the potential for local activation of Vgamma9Vdelta2 T cells within the tumor environment to increase potency and achieve objective responses during cancer therapy. The gamma delta T cells and especially the Vgamma9Vdelta2 T cell subset, have the potential to overcome many problems in cancer therapy especially for tumors with no known treatment, lacking tumor-specific antigens for targeting by antibodies and CAR-T, or unresponsive to immune checkpoint inhibitors. Translation of amazing work from many laboratories studying gamma delta T cells is needed to fulfill the promise of effective and safe cancer immunotherapy.

Author Info: (1) American Gene Technologies International Inc., Rockville, MD, United States. (2) American Gene Technologies International Inc., Rockville, MD, United States. (3) American Gene Technologies International

Author Info: (1) American Gene Technologies International Inc., Rockville, MD, United States. (2) American Gene Technologies International Inc., Rockville, MD, United States. (3) American Gene Technologies International Inc., Rockville, MD, United States. (4) American Gene Technologies International Inc., Rockville, MD, United States. (5) Department of Medicine, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, United States. (6) Institute of Human Virology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States. (7) American Gene Technologies International Inc., Rockville, MD, United States.

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In Vivo Study of Natural Killer (NK) Cell Cytotoxicity Against Cholangiocarcinoma in a Nude Mouse Model

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BACKGROUND/AIM: Natural killer (NK) cells are one of the lymphocytes clinically used for various cancer types. Cytotoxicity of NK cells to cholangiocarcinoma (CC), however, has not yet been studied. Nor NK cell therapy against CC has been clinically applied. In this study, relevance of NK cell therapy for anti-tumor efficacy against CC was pre-clinically investigated. MATERIALS AND METHODS: Human HuCCT-1 cells, an intrahepatic CC cell line, were xenografted into nude mice. The HuCCT-1 tumor-bearing nude mice then received multiple infusions of ex vivo-expanded human NK cells (SMT01) and in vivo cytotoxic activity of the NK cells against the CC cells was evaluated. RESULTS: SMT01 infusion resulted in significant inhibition of the CC tumor growth. Body weight of the mice administrated with chemotherapy was found to be maintained at the lowest level among all treatment groups while all the SMT01 infusion groups well maintained their body weight. CONCLUSION: The present in vivo study demonstrates that NK cells contain cytolytic activity against cholangiocarcinoma and show beneficial effect of NK cell therapy in relevance to quality of life. Further investigation of the NK cell-based immunotherapy can be useful to determine cancer therapeutics for the specific tumor.

Author Info: (1) Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea. (2) Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of

Author Info: (1) Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea. (2) Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea. Postgraduate School of Nano Science and Technology, Yonsei University, Seoul, Republic of Korea. (3) Research Institute of SMT Bio, SMT Bio Co., Ltd., Seoul, Republic of Korea. (4) Research Institute of SMT Bio, SMT Bio Co., Ltd., Seoul, Republic of Korea. (5) Research Institute of SMT Bio, SMT Bio Co., Ltd., Seoul, Republic of Korea. (6) Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea. (7) Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea yjung21@gmail.com swoopark@yuhs.ac. (8) Research Institute of SMT Bio, SMT Bio Co., Ltd., Seoul, Republic of Korea yjung21@gmail.com swoopark@yuhs.ac.

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A novel potential effective strategy for enhancing the antitumor immune response in breast cancer patients using a viable cancer cell-dendritic cell-based vaccine

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Dendritic cells (DCs) have been used in a number of clinical trials for cancer immunotherapy; however, they have achieved limited success in solid tumors. Consequently the aim of the present study was to identify a novel potential immunotherapeutic target for breast cancer patients through in vitro optimization of a viable DC-based vaccine. Immature DCs were primed by viable MCF-7 breast cancer cells and the activity and maturation of DCs were assessed through measuring CD83, CD86 and major histocompatibility complex (MHC)-II expression, in addition to different T cell subpopulations, namely CD4(+) T cells, CD8(+) T cells, and CD4(+)CD25(+) forkhead box protein 3 (Foxp3)(+) regulatory T cells (Tregs), by flow cytometric analysis. Foxp3 level was also measured by enzyme-linked immunosorbent assay (ELISA) in addition to reverse-transcription quantitative polymerase chain reaction. The levels of interleukin-12 (IL-12) and interferon-gamma (IFN-gamma) were determined by ELISA. Finally, the cytotoxicity of cytotoxic T lymphocytes (CTLs) was evaluated through measuring lactate dehydrogenase (LDH) release by ELISA. The results demonstrated that CD83(+), CD86(+) and MHC-II(+) DCs were significantly elevated (P<0.001) following priming with breast cancer cells. In addition, there was increased activation of CD4(+) and CD8(+) T-cells, with a significant decrease of CD4(+)CD25(+)Foxp3(+) Tregs (P<0.001). Furthermore, a significant downregulation of FOXP3 gene expression (P<0.001) was identified, and a significant decrease in the level of its protein following activation (P<0.001) was demonstrated by ELISA. Additionally, significant increases in the secretion of IL-12 and IFN-gamma (P=0.001) were observed. LDH release was significantly increased (P<0.001), indicating a marked cytotoxicity of CTLs against cancer cells. Therefore viable breast cancer cell-DC-based vaccines could expose an innovative avenue for a novel breast cancer immunotherapy.

Author Info: (1) Medical Biochemistry and Molecular Biology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11976, Egypt. (2) Medical Biochemistry and Molecular Biology

Author Info: (1) Medical Biochemistry and Molecular Biology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11976, Egypt. (2) Medical Biochemistry and Molecular Biology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11976, Egypt. (3) Department of Clinical Pathology, National Cancer Institute, Cairo University, Cairo 11976, Egypt. (4) Department of Pathology, National Cancer Institute, Cairo University, Cairo 11976, Egypt. (5) Department of Zoology, Faculty of Science, Tanta University, Tanta, Gharbia 31511, Egypt. (6) Medical Biochemistry and Molecular Biology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11976, Egypt.

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Decitabine Enhances Vgamma9Vdelta2 T Cell-Mediated Cytotoxic Effects on Osteosarcoma Cells via the NKG2DL-NKG2D Axis

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gammadelta T cell-based immunotherapy for osteosarcoma (OS) has shown limited success thus far. DNA-demethylating agents not only induce tumor cell death but also have an immunomodulatory function. In this study, we have assessed the potential benefit of combining decitabine (DAC, a DNA demethylation drug) and gammadelta T cells for OS immunotherapy. DAC increased the expression of natural killer group 2D (NKG2D) ligands (NKG2DLs), including major histocompatibility complex class I-related chains B (MICB) and UL16-binding protein 1 (ULBP1), on the OS cell surface, making the cells more sensitive to recognition and destruction by cytotoxic gammadelta T cells. The upregulation of MICB and ULBP1 was due to promoter DNA demethylation. Importantly, the killing of OS cells by gammadelta T cells was partially reversed by blocking the NKG2D receptor, suggesting that the gammadelta T cell-mediated cytolysis of DAC-pretreated OS cells was mainly dependent on the NKG2D-NKG2DL axis. The in vivo results were consistent with the in vitro results. In summary, DAC could upregulate MICB and ULBP1 expression in OS cells, and combination treatment involving gammadelta T cell immunotherapy and DAC could be used to enhance the cytotoxic killing of OS cells by gammadelta T cells.

Author Info: (1) Centre for Orthopaedic Research, Orthopedics Research Institute of Zhejiang University, Department of Orthopaedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou

Author Info: (1) Centre for Orthopaedic Research, Orthopedics Research Institute of Zhejiang University, Department of Orthopaedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. (2) Centre for Orthopaedic Research, Orthopedics Research Institute of Zhejiang University, Department of Orthopaedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. (3) Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Key Laboratory of Molecular Biology in Medical Sciences, National Ministry of Education, Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. (4) Centre for Orthopaedic Research, Orthopedics Research Institute of Zhejiang University, Department of Orthopaedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. (5) Centre for Orthopaedic Research, Orthopedics Research Institute of Zhejiang University, Department of Orthopaedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. (6) Centre for Orthopaedic Research, Orthopedics Research Institute of Zhejiang University, Department of Orthopaedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. (7) Centre for Orthopaedic Research, Orthopedics Research Institute of Zhejiang University, Department of Orthopaedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. (8) Centre for Orthopaedic Research, Orthopedics Research Institute of Zhejiang University, Department of Orthopaedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. (9) Centre for Orthopaedic Research, Orthopedics Research Institute of Zhejiang University, Department of Orthopaedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. (10) Centre for Orthopaedic Research, Orthopedics Research Institute of Zhejiang University, Department of Orthopaedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. (11) Centre for Orthopaedic Research, Orthopedics Research Institute of Zhejiang University, Department of Orthopaedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.

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Ilixadencel - an Allogeneic Cell-Based Anticancer Immune Primer for Intratumoral Administration

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Intratumoral administration of an immune primer is a therapeutic vaccine strategy aimed to trigger dendritic cell (DC)-mediated cross-presentation of cell-associated tumor antigens to cytotoxic CD8(+) T cells without the need for tumor antigen characterization. The prevailing view is that these cross-presenting DCs have to be directly activated by pathogen-associated molecular patterns (PAMPS), including Toll-like receptor ligands or live microbial agents like oncolytic viruses. Emerging data are however challenging this view, indicating that the cross-presenting machinery in DCs is suboptimally activated by direct PAMP recognition, and that endogenous inflammatory factors are the main drivers of DC-mediated cross-presentation within the tumor. Here we present preclinical mode of action data, CMC and regulatory data, as well as initial clinical data on ilixadencel. This cell-based drug product is an off-the-shelf immune primer, consisting of pro-inflammatory allogeneic DCs secreting high amounts of pro-inflammatory chemokines and cytokines at the time of intratumoral administration. The mechanism of action of ilixadencel is to induce recruitment and activation of endogenous immune cells, including NK cells that subsequently promotes cross-presentation of cell-associated tumor antigens by co-recruited DCs.

Author Info: (1) Immunicum AB, Grafiska Vagen 2, 412 63, Gothenburg, Sweden. alex.karlsson-parra@immunicum.com. Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjolds Vag 20

Author Info: (1) Immunicum AB, Grafiska Vagen 2, 412 63, Gothenburg, Sweden. alex.karlsson-parra@immunicum.com. Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjolds Vag 20, 752 37, Uppsala, Sweden. alex.karlsson-parra@immunicum.com. (2) Immunicum AB, Grafiska Vagen 2, 412 63, Gothenburg, Sweden. (3) Immunicum AB, Grafiska Vagen 2, 412 63, Gothenburg, Sweden. (4) Immunicum AB, Grafiska Vagen 2, 412 63, Gothenburg, Sweden. (5) Immunicum AB, Grafiska Vagen 2, 412 63, Gothenburg, Sweden. (6) Immunicum AB, Grafiska Vagen 2, 412 63, Gothenburg, Sweden. (7) Immunicum AB, Grafiska Vagen 2, 412 63, Gothenburg, Sweden.

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