Journal Articles

Cellular immunotherapy

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

Cytotoxic activity of effector T cells against cholangiocarcinoma is enhanced by self-differentiated monocyte-derived dendritic cells

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Cholangiocarcinoma (CCA) is a cancer of the bile ducts that is associated with poor prognosis and poor treatment outcome. Approximately one-third of CCA patients can undergo surgery, but the recurrence rate is high and chemotherapy often cannot satisfactorily prolong survival. Cellular immunotherapy based on adoptive T-cell transfer is a potential treatment for CCA; however, the development of this technology and the search for an appropriate tumor-associated antigen are still ongoing. To enhance the cytotoxic activity of effector T cells against CCA, we developed self-differentiated monocyte-derived dendritic cells (SD-DC) presenting cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A), which is an overexpressed protein that plays a role in the regulation of tumor growth to activate T cells for CCA cell killing. Dendritic cells (DCs) transduced with lentivirus harboring tri-cistronic cDNA sequences (SD-DC-PR) could produce granulocyte-macrophage colony-stimulating factor, interleukin-4, and PRKAR1A. SD-DC showed similar phenotypes to those of DCs derived by conventional method. Autologous effector T cells (CD3+, CD8+) activated by SD-DC-PR exhibited greater cytotoxic activity against CCA than those activated by conventionally-derived DCs. Effector T cells activated by SD-DC-PR killed 60% of CCA cells at an effector-to-target ratio of 15:1, which is approximately twofold greater than the cell killing performance of those stimulated with control DC. The cytotoxic activities of effector T cells activated by SD-DC-PR against CCA cells were significantly associated with the expression levels of PRKR1A in CCA cells. This finding that SD-DC-PR effectively stimulated autologous effector T cells to kill CCA cells may help to accelerate the development of novel therapies for treating CCA.

Author Info: (1) Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand. Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj

Author Info: (1) Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand. Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand. Center of Excellence in Bioresources for Agriculture, Industry and Medicine, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand. (2) Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand. Graduate Program in Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. (3) Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand. (4) Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand. (5) Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand. Graduate Program in Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. (6) Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand. (7) Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. (8) Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand. pathai.yen@mahidol.ac.th.

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Junctional adhesion molecules mediate transendothelial migration of dendritic cell vaccine in cancer immunotherapy

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In vitro generated dendritic cells (DCs) have been studied in cancer immunotherapy for decades. However, the detailed molecular mechanism underlying transendothelial migration (TEM) of DC vaccine across the endothelial barrier to regional lymph nodes (LNs) remains largely unknown. Here, we found that junctional adhesion molecule (JAM)-Like (JAML) is involved in the TEM of mouse bone marrow-derived DCs (BMDCs). Treatment with an anti-JAML antibody or JAML knock-down significantly reduced the TEM activity of BMDCs, leading to impairment of DC-based cancer immunotherapy. We found that the interaction of JAML of BMDCs with the coxsackie and adenovirus receptor of endothelial cells plays a crucial role in the TEM of BMDCs. On the other hand, human monocyte-derived DCs (MoDCs) did not express the JAML protein but still showed normal TEM activity. We found that MoDCs express only JAM1 and that the homophilic interaction of JAM1 is essential for MoDC TEM across a HUVEC monolayer. Our findings suggest that specific JAM family members play an important role in the TEM of in vitro-generated mouse and human DCs from the inoculation site to regional LNs in DC-based cancer immunotherapy.

Author Info: (1) Department of Biological Sciences, Science Research Center (SRC) for Immune Research on Non-lymphoid Organ (CIRNO), Sungkyunkwan University, Jangan-gu, Suwon, Gyeonggi-do 16419, South Korea. (2)

Author Info: (1) Department of Biological Sciences, Science Research Center (SRC) for Immune Research on Non-lymphoid Organ (CIRNO), Sungkyunkwan University, Jangan-gu, Suwon, Gyeonggi-do 16419, South Korea. (2) Department of Biological Sciences, Science Research Center (SRC) for Immune Research on Non-lymphoid Organ (CIRNO), Sungkyunkwan University, Jangan-gu, Suwon, Gyeonggi-do 16419, South Korea. (3) Department of Biological Sciences, Science Research Center (SRC) for Immune Research on Non-lymphoid Organ (CIRNO), Sungkyunkwan University, Jangan-gu, Suwon, Gyeonggi-do 16419, South Korea. (4) Department of Biological Sciences, Science Research Center (SRC) for Immune Research on Non-lymphoid Organ (CIRNO), Sungkyunkwan University, Jangan-gu, Suwon, Gyeonggi-do 16419, South Korea. Electronic address: ysbae04@skku.edu.

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Fusion of Dendritic Cells and Cancer-Associated Fibroblasts for Activation of Anti-Tumor Cytotoxic T Lymphocytes

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Here we explored the fusion of dendritic cells (DCs), potent antigen-presenting cells that initiate primary immune responses, with cancer-associated fibroblasts (CAFs), which are a stromal component needed for tumor progression, with the aim of stimulating T cells to inhibit tumor growth. Dendritic cells from the bone marrow of BALB/c mice were co-cultured with CAFs from H22 mouse hepatoma cells. CAFs were found to express fibroblast activation protein and alpha-smooth muscle actin by flow cytometry, Western blotting and immunofluorescence. Polyethylene glycol was added to the co-culture medium to encourage fusion, and the ability of the resulting fusion cells to produce TNF-alpha, IL-1beta, IL-6, and IL-12p70 was confirmed using ELISA. These fusion cells efficiently stimulated T lymphocytes in vitro, causing them to generate IFN-alpha and IFN-gamma. T cells activated by DC/CAF fusion cells led to strong CTL response against CAFs in vitro. The activated T cells also inhibited growth of H22 xenografts in vivo. These results indicate that DC/CAF fusion cells show potential for stimulating T cells as a novel anti-tumor vaccine.

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

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

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Challenges of NK cell-based immunotherapy in the new era

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Natural killer cells (NKs) have a great potential for cancer immunotherapy because they can rapidly and directly kill transformed cells in the absence of antigen presensitization. Various cellular sources, including peripheral blood mononuclear cells (PBMCs), stem cells, and NK cell lines, have been used for producing NK cells. In particular, NK cells that expanded from allogeneic PBMCs exhibit better efficacy than those that did not. However, considering the safety, activities, and reliability of the cell products, researchers must develop an optimal protocol for producing NK cells from PBMCs in the manufacture setting and clinical therapeutic regimen. In this review, the challenges on NK cell-based therapeutic approaches and clinical outcomes are discussed.

Author Info: (1) Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Sciences

Author Info: (1) Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, 230027, China. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, 230027, China. (2) Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, 230027, China. xiaow@ustc.edu.cn. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, 230027, China. xiaow@ustc.edu.cn. (3) Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, 230027, China. tzg@ustc.edu.cn. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, 230027, China. tzg@ustc.edu.cn.

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A novel allogeneic off-the-shelf dendritic cell vaccine for post-remission treatment of elderly patients with acute myeloid leukemia

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In elderly acute myeloid leukemia (AML) patients post-remission treatment options are associated with high comorbidity rates and poor survival. Dendritic cell (DC)-based immunotherapy is a promising alternative treatment strategy. A novel allogeneic DC vaccine, DCP-001, was developed from an AML-derived cell line that uniquely combines the positive features of allogeneic DC vaccines and expression of multi-leukemia-associated antigens. Here, we present data from a phase I study conducted with DCP-001 in 12 advanced-stage elderly AML patients. Patients enrolled were in complete remission (CR1/CR2) (n = 5) or had smoldering disease (n = 7). All patients were at high risk of relapse and ineligible for post-remission intensification therapies. A standard 3 + 3 dose escalation design with extension to six patients in the highest dose was performed. Patients received four biweekly intradermal DCP-001 injections at different dose levels (10, 25, and 50 million cells DCP-001) and were monitored for clinical and immunological responses. Primary objectives of the study (feasibility and safety) were achieved with 10/12 patients completing the vaccination program. Treatment was well tolerated. A clear-cut distinction between patients with and without detectable circulating leukemic blasts during the vaccination period was noted. Patients with no circulating blasts showed an unusually prolonged survival [median overall survival 36 months (range 7-63) from the start of vaccination] whereas patients with circulating blasts, died within 6 months. Long-term survival was correlated with maintained T cell levels and induction of multi-functional immune responses. It is concluded that DCP-001 in elderly AML patients is safe, feasible and generates both cellular and humoral immune responses.

Author Info: (1) Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (2) DCPrime BV, Galileiweg 8, 233

Author Info: (1) Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (2) DCPrime BV, Galileiweg 8, 2333 BD, Leiden, The Netherlands. (3) Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. (4) DCPrime BV, Galileiweg 8, 2333 BD, Leiden, The Netherlands. (5) Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (6) Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (7) Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (8) DCPrime BV, Galileiweg 8, 2333 BD, Leiden, The Netherlands. (9) Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (10) DCPrime BV, Galileiweg 8, 2333 BD, Leiden, The Netherlands. (11) Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. td.degruijl@vumc.nl.

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Combination of Cytokine-Induced Killer Cells and Programmed Cell Death-1 Blockade Works Synergistically to Enhance Therapeutic Efficacy in Metastatic Renal Cell Carcinoma and Non-Small Cell Lung Cancer

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Introduction: Programmed cell death-1 (PD-1) inhibition therapy has changed the treatment paradigm of metastatic renal cell carcinoma (MRCC) and non-small cell lung cancer (NSCLC). However, attempts to use the drug as a single agent have achieved only limited clinical success. To further enhance the clinical benefits of monotherapy, combination therapies will likely be necessary. Cytokine-induced killer (CIK) cells are a heterogeneous subset of ex vivo expanded T lymphocytes that have been shown to prolong the survival of cancer patients. We are conducting a study to evaluate the efficacy of PD-1 inhibitor in combination with CIK cells in relapsed/refractory MRCC and NSCLC and to analyze potential biomarkers to predict which patients will benefit most from the combined therapy. Case presentation: The results of two patients treated in an ongoing clinical trial for MRCC and NSCLC are described here. The tumor biopsy from Patient 1 exhibited moderate CD3(+) T cell infiltration, but no PD-1 or PD-L1 expression. The tumor cells from Patient 2 strongly expressed PD-L1, and there was extensive tumor infiltration by CD3(+) T cells; however, no PD-1 staining was seen. Non-synonymous single nucleotide variant (nsSNVs), along with higher indel mutations, in Patient 1 and nsSNVs along with higher tumor mutation burden in Patient 2 correlate with tumor-infiltrating CD3(+) lymphocyte density. Patient 1 achieved a complete response, and Patient 2 achieved a near-complete response. Conclusion: A PD-1 inhibitor in combination with CIK cells led to potent antitumor activity in MRCC and NSCLC; CD3(+) T cell infiltration in baseline tumor biopsies is a potential predictive biomarker. This approach is being further investigated in an ongoing phase I trial.

Author Info: (1) Affiliated Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. (2) Affiliated Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. (3) Fred Hutchinson

Author Info: (1) Affiliated Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. (2) Affiliated Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. (3) Fred Hutchinson Cancer Research Center, Seattle, WA, United States. (4) Affiliated Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. (5) Affiliated Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. (6) Affiliated Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.

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Naturally produced type I IFNs enhance human myeloid dendritic cell maturation and IL-12p70 production and mediate elevated effector functions in innate and adaptive immune cells

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There has recently been a paradigm shift in the field of dendritic cell (DC)-based immunotherapy, where several clinical studies have confirmed the feasibility and advantageousness of using directly isolated human blood-derived DCs over in vitro differentiated subsets. There are two major DC subsets found in blood; plasmacytoid DCs (pDCs) and myeloid DCs (mDCs), and both have been tested clinically. CD1c(+) mDCs are highly efficient antigen-presenting cells that have the ability to secrete IL-12p70, while pDCs are professional IFN-alpha-secreting cells that are shown to induce innate immune responses in melanoma patients. Hence, combining mDCs and pDCs poses as an attractive, multi-functional vaccine approach. However, type I IFNs have been reported to inhibit IL-12p70 production and mDC-induced T-cell activation. In this study, we investigate the effect of IFN-alpha on mDC maturation and function. We demonstrate that both recombinant IFN-alpha and activated pDCs strongly enhance mDC maturation and increase IL-12p70 production. Co-cultured mDCs and pDCs additionally have beneficial effect on NK and NKT-cell activation and also enhances IFN-gamma production by allogeneic T cells. In contrast, the presence of type I IFNs reduces the proliferative T-cell response. The mere presence of a small fraction of activated pDCs is sufficient for these effects and the required ratio between the subsets is non-stringent. Taken together, these results support the usage of mDCs and pDCs combined into one immunotherapeutic vaccine with broad immunostimulatory features.

Author Info: (1) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Geert Grooteplein 26/28, 6525 GA, Nijmegen, The Netherlands. Department of Oncology-Pathology, Cancer Center

Author Info: (1) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Geert Grooteplein 26/28, 6525 GA, Nijmegen, The Netherlands. Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden. (2) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Geert Grooteplein 26/28, 6525 GA, Nijmegen, The Netherlands. (3) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Geert Grooteplein 26/28, 6525 GA, Nijmegen, The Netherlands. (4) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Geert Grooteplein 26/28, 6525 GA, Nijmegen, The Netherlands. (5) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Geert Grooteplein 26/28, 6525 GA, Nijmegen, The Netherlands. (6) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Geert Grooteplein 26/28, 6525 GA, Nijmegen, The Netherlands. (7) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Geert Grooteplein 26/28, 6525 GA, Nijmegen, The Netherlands. (8) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Geert Grooteplein 26/28, 6525 GA, Nijmegen, The Netherlands. Allergic Inflammation Discovery Performance Unit, Respiratory Therapy Area, GlaxoSmithKline, Stevenage, United Kingdom. (9) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Geert Grooteplein 26/28, 6525 GA, Nijmegen, The Netherlands. (10) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Geert Grooteplein 26/28, 6525 GA, Nijmegen, The Netherlands. Jolanda.deVries@radboudumc.nl. Department of Medical Oncology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands. Jolanda.deVries@radboudumc.nl.

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Cytokines Produced by Dendritic Cells Administered Intratumorally Correlate with Clinical Outcome in Patients with Diverse Cancers

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Purpose: Dendritic cells (DC) initiate adaptive immune responses through the uptake and presentation of antigenic material. In preclinical studies, intratumorally injected activated DCs (aDCs; DCVax-Direct) were superior to immature DCs in rejecting tumors from mice.Experimental Design: This single-arm, open-label phase I clinical trial evaluated the safety and efficacy of aDCs, administered intratumorally, in patients with solid tumors. Three dose levels (2 million, 6 million, and 15 million aDCs per injection) were tested using a standard 3 + 3 dose-escalation trial design. Feasibility, immunogenicity, changes to the tumor microenvironment after direct injection, and survival were evaluated. We also investigated cytokine production of aDCs prior to injection.Results: In total, 39 of the 40 enrolled patients were evaluable. The injections of aDCs were well tolerated with no dose-limiting toxicities. Increased lymphocyte infiltration was observed in 54% of assessed patients. Stable disease (SD; best response) at week 8 was associated with increased overall survival. Increased secretion of interleukin (IL)-8 and IL12p40 by aDCs was significantly associated with survival (P = 0.023 and 0.024, respectively). Increased TNFalpha levels correlated positively with SD at week 8 (P < 0.01).Conclusions: Intratumoral aDC injections were feasible and safe. Increased production of specific cytokines was correlated with SD and prolonged survival, demonstrating a link between the functional profile of aDCs prior to injection and patient outcomes. Clin Cancer Res; 1-12. (c)2018 AACR.

Author Info: (1) Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. vsubbiah@mdanderson.org. (2) Department of Interventional

Author Info: (1) Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. vsubbiah@mdanderson.org. (2) Department of Interventional Radiology, Division of Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas. (3) Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. (4) Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. (5) Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. (6) Cognate Bioservices, Memphis, Tennessee. (7) Cognate Bioservices, Memphis, Tennessee. (8) Cognate Bioservices, Memphis, Tennessee. (9) Department of Pathology and Laboratory Medicine, UT Health, University of Texas Health Science Center, Houston, Texas. (10) Department of Pathology and Laboratory Medicine, UT Health, University of Texas Health Science Center, Houston, Texas. (11) Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. (12) Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. (13) Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. (14) Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. (15) Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. (16) Cell Therapy Labs, GMP Laboratory, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas. (17) Northwest Biotherapeutics, Inc., Bethesda, Maryland.

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Expanded CD56superbrightCD16+ NK cells from ovarian cancer patients are cytotoxic against autologous tumor in a patient-derived xenograft murine model

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Natural Killer (NK) cells are useful for cancer immunotherapy and have proven clinically effective against hematological malignancies. However, immunotherapies for poor prognosis solid malignancies, including ovarian cancer, have not been as successful due to immunosuppression by solid tumors. Although re-arming patients' own NK cells to treat cancer is an attractive option, success of that strategy is limited by the impaired function of NK cells from cancer patients and by inhibition by self-MHC. In this study, we show that expansion converts healthy donor and immunosuppressed ovarian cancer patient NK cells to a cytotoxic CD56superbrightCD16+ subset with activation state and antitumor functions that increase with CD56 brightness. We investigated whether these expanded NK cells may overcome the limitations of autologous NK cell therapy against solid tumors. Peripheral blood- and ascites-derived NK cells from ovarian cancer patients were expanded then adoptively transferred into cell-line and autologous patient-derived xenograft models of human ovarian cancer. Expanded ovarian cancer patient NK cells reduced the burden of established tumors and prolonged survival. These results suggest that CD56bright NK cells harbour superior antitumor function compared to CD56dim cells. Thus, NK cell expansion may overcome limitations on autologous NK cell therapy by converting the patient's NK cells to a cytotoxic subset that exerts a therapeutic effect against autologous tumor. These findings suggest that the value of expanded autologous NK cell therapy for ovarian cancer and other solid malignancies should be clinically assessed.

Author Info: (1) Pathology & Molecular Medicine, McMaster University. (2) Pathology & Molecular Medicine, McMaster University. (3) Pathology & Molecular Medicine, McMaster University. (4) Pathology & Molecular

Author Info: (1) Pathology & Molecular Medicine, McMaster University. (2) Pathology & Molecular Medicine, McMaster University. (3) Pathology & Molecular Medicine, McMaster University. (4) Pathology & Molecular Medicine, McMaster University. (5) Pathology & Molecular Medicine, McMaster University. (6) Pathology & Molecular Medicine, McMaster University. (7) Oncology, McMaster University. (8) Pathology and Molecular Medicine, McMaster University. (9) Heme/Onc/BMT, Nationwide Children's Hospital. (10) Oncology, McMaster University. (11) Pathology & Molecular Medicine, McMaster University ashkara@mcmaster.ca.

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Current strategies exploiting NK-cell therapy to treat haematologic malignancies

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Natural killer (NK) cells recognize targets that have been changed via malignant transformation or infection. Previously, NK cells were thought to be short-lived, but we now know that NK cells can be long-lived and remember past exposures in response to CMV. NK cells use a plethora of activating and inhibitory receptors to recognize these changes and attack targets, but tumour cells often evade NK cells. Therefore, major efforts are being made to hone in on NK cell antitumour properties in immunotherapy. In the clinical setting, haploidentical NK cells can be adoptively transferred to help treat cancer. To expand NK cells in vivo and enhance tumour targeting, IL-15 is being tested in combination with a glycogen synthase kinase (GSK) 3 inhibitor (CHIR99021), an inhibitor that has been shown to expand mature, highly functional NK cells capable of killing multiple tumour targets. One major limitation to NK cell therapy is lack of specificity. To address this concern, bispecific or trispecific engagers that target NK cells to the tumour and an ADAM17 inhibitor that prevents CD16 shedding after NK cell activation are being tested. Additionally, monoclonal antibodies are being designed to redirect the inhibitory signals that limit NK cell functionality. Further understanding of the biology of NK cells will inform strategies to exploit NK cells for therapeutic purposes.

Author Info: (1) Department of Medicine, Division of Hematology, Oncology, and Transplantation, Masonic Cancer Center, University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota. Medical Scientist Training Program

Author Info: (1) Department of Medicine, Division of Hematology, Oncology, and Transplantation, Masonic Cancer Center, University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota. Medical Scientist Training Program, University of Minnesota, Minneapolis, Minnesota. (2) Department of Medicine, Division of Hematology, Oncology, and Transplantation, Masonic Cancer Center, University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota.

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