Journal Articles

Cellular immunotherapy

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

hIL-15-gene modified human natural killer cells (NKL-IL15) exhibit anti-human leukemia functions

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PURPOSE: Natural killer (NK) cells can kill transformed cells and represent anti-tumor activities for improving the immunotherapy of cancer. In previous works, we established human interleukin-15 (hIL-15) gene-modified NKL cells (NKL-IL15) and demonstrated their efficiency against human hepatocarcinoma cells (HCCs) in vitro and in vivo. To further assess the applicability of NKL-IL15 cells in adoptive cellular immunotherapy for human leukemia, here we report their natural cytotoxicity against leukemia in vitro and in vivo. METHODS: Flow cytometry, ELISA and MTT methods were performed for molecular expression, cell proliferation and cytotoxicity assays. Leukemia xenograft NOD/SCID mice were established by subcutaneous injection with K562 cells, and then treated with irradiated NKL cells. RESULTS: We found NKL-IL15 cells displayed a significant high cytolysis activity against both human leukemia cell lines and primary leukemia cells from patients, accompanied with up-regulated expression of molecules related to NK cell cytotoxicity such as perforin, granzyme B and NKp80. Moreover, cytokines secreted by NKL-IL15 cells, including TNF-alpha and IFN-gamma, could induce the expression of NKG2D ligands on target cells, which increased the susceptibility of leukemia cells to NK cell-mediated cytolysis. Encouragingly, NKL-IL15 cells significantly inhibited the growth of leukemia cells in xenografted NOD/SCID mice and prolonged the survival of tumor-bearing mice dramatically. Furthermore, NKL-IL15 cells displayed stimulatory effects on hPBMCs, indicating the immunesuppressive status of leukemia patients could be improved by NKL-IL15 cell treatment. CONCLUSIONS: These results provided evidence that IL-15 gene-modification could augment NK cell-mediated anti-human leukemia function, which would improve primary NK cell-based immunotherapy for leukemia in future.

Author Info: (1) Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan, China. (2) Institute of Immunopharmaceutical Sciences, School of Pharmaceutical

Author Info: (1) Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan, China. (2) Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan, China. (3) Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan, China. (4) Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan, China. zhangj65@sdu.edu.cn.

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Recommendations for managing PD-1 blockade in the context of allogeneic HCT in Hodgkin lymphoma: taming a necessary evil

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PD-1 blockade is an effective therapy in relapsed/refractory (R/R) classical Hodgkin Lymphoma (cHL) who have relapsed after or are ineligible for autologous hematopoietic cell transplantation (HCT). While single-agent anti-PD-1 monoclonal antibodies (mAbs) are associated with high response rates and durable remissions, available results to date suggest that a large majority of patients will eventually progress on therapy. Many of these patients are potential candidates for allogeneic HCT (allo-HCT) after receiving anti-PD-1 mAbs, and allo-HCT remains for now the only treatment with demonstrated curative potential in this setting. However, initial reports suggested that allo-HCT in this setting may be associated with increased risk of early transplant-related toxicity, likely driven by lingering effects of PD-1 blockade. Furthermore, many patients with R/R cHL who undergo allo-HCT will relapse after transplantation, most often with limited treatment options. Here again PD-1 blockade appears to yield high response rates, but with an increased risk of attendant immune toxicity. Many questions remain regarding the use of PD-1 blockade before or after allo-HCT, especially in relation to the feasibility, outcome, optimal timing, and method of allo-HCT after PD-1 blockade. Despite the scarcity of prospective data, these questions are unavoidable and must be tackled by clinicians in the routine care of patients with advanced cHL. We provide consensus recommendations of a working group based on available data and experience, in an effort to help guide treatment decisions until more definitive data are obtained.

Author Info: (1) CHRU Lille, Lille, France. (2) Dana-Farber Cancer Institute, Boston, MA, United States. (3) The Ohio State University, Columbus, OH, United States. (4) Dana-Farber Cancer

Author Info: (1) CHRU Lille, Lille, France. (2) Dana-Farber Cancer Institute, Boston, MA, United States. (3) The Ohio State University, Columbus, OH, United States. (4) Dana-Farber Cancer Institute, Boston, MA, United States. (5) CHU Rennes, Rennes, France. (6) CHRU Lille, Lille, France. (7) University of Colorado, Aurora, CO, United States bradley.haverkos@ucdenver.edu.

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CD44v6 as innovative sarcoma target for CAR-redirected CIK cells

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Purpose of our study was to explore a new immunotherapy for high grade soft tissue sarcomas (STS) based on cytokine-induced killer cells (CIK) redirected with a chimeric antigen receptor (CAR) against the tumor-promoting antigen CD44v6. We aimed at generating bipotential killers, combining the CAR specificity with the intrinsic tumor-killing ability of CIK cells (CAR(+).CIK). We set a patient-derived experimental platform. CAR(+).CIK were generated by transduction of CIK precursors with a lentiviral vector encoding for anti-CD44v6-CAR. CAR(+).CIK were characterized and assessed in vitro against multiple histotypes of patient-derived STS. The anti-sarcoma activity of CAR(+).CIK was confirmed in a STS xenograft model. CD44v6 was expressed by 40% (11/27) of patient-derived STS. CAR(+).CIK were efficiently expanded from patients (n = 12) and killed multiple histotypes of STS (including autologous targets, n = 4). The killing activity was significantly higher compared with unmodified CIK, especially at low effector/target (E/T) ratios: 98% vs 82% (E/T = 10:1) and 68% vs 26% (1:4), (p<0.0001). Specificity of tumor killing was confirmed by blocking with anti-CD44v6 antibody. CAR(+).CIK produced higher amounts of IL6 and IFN-gamma compared to control CIK. CAR(+).CIK were highly active in mice bearing subcutaneous STS xenografts, with significant delay of tumor growth (p<0.0001) without toxicities. We report first evidence of CAR(+).CIK's activity against high grade STS and propose CD44v6 as an innovative target in this setting. CIK are a valuable platform for the translation of CAR-based strategies to challenging field of solid tumors. Our findings support the exploration of CAR(+).CIK in clinical trials against high grade STS.

Author Info: (1) Department of Oncology, University of Torino, Torino, Italy. Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy. (2) Innovative Immunotherapies Unit, IRCCS

Author Info: (1) Department of Oncology, University of Torino, Torino, Italy. Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy. (2) Innovative Immunotherapies Unit, IRCCS San Raffaele Hospital Scientific Institute, Milano, Italy. (3) Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy. (4) Department of Oncology, University of Torino, Torino, Italy. (5) Department of Oncology, University of Torino, Torino, Italy. (6) Department of Oncology, University of Torino, Torino, Italy. Laboratory of Gene Transfer, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy. (7) Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy. (8) Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy. (9) Department of Oncology, University of Torino, Torino, Italy. (10) Department of Oncology, University of Torino, Torino, Italy. (11) Pathology Unit, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, (TO), Italy. (12) Department of Oncology, University of Torino, Torino, Italy. Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy. (13) Department of Oncology, University of Torino, Torino, Italy. Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy. (14) Department of Oncology, University of Torino, Torino, Italy. Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy. (15) Innovative Immunotherapies Unit, IRCCS San Raffaele Hospital Scientific Institute, Milano, Italy. Vita-Salute San Raffaele University, Milano, Italy. (16) Department of Oncology, University of Torino, Torino, Italy. Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy.

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In situ delivery of allogeneic natural killer cell (NK) combined with Cetuximab in liver metastases of gastrointestinal carcinoma: A phase I clinical trial

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Despite successful introduction of NK-based cellular therapy in the treatment of myeloid leukemia, the potential use of NK alloreactivity in solid malignancies is still elusive. We performed a phase I clinical trial to assess the safety and efficacy of in situ delivery of allogeneic NK cells combined with cetuximab in liver metastasis of gastrointestinal origin. The conditioning chemotherapy was administrated before the allogeneic NK cells injection via hepatic artery. Three escalating doses were tested (3.10(6), 8.10(6) and 12.10(6) NK cells/kg) following by a high-dose interleukin-2 (IL-2). Cetuximab was administered intravenously every week for 7 weeks. Nine patients with liver metastases of colorectal or pancreatic cancers were included, three per dose level. Hepatic artery injection was successfully performed in all patients with no report of dose-limiting toxicity. Two patients had febrile aplasia requiring a short-term antibiotherapy. Grade 3/4 anemia and thrombopenia were also observed related to the chemotherapy. Objective clinical responses were documented in 3 patients and among them 2 occurred in patients injected with cell products harboring two KIR ligand mismatches and one in a patient with one KIR ligand mismatch. Immune monitoring revealed that most patients presented an increase but transient of IL-15 and IL-7 cytokines levels one week after chemotherapy. Furthermore, a high expansion of FoxP3(+)regulatory T cells and PD-1(+) T cells was observed in all patients, related to IL-2 administration. Our results demonstrated that combining allogeneic NK cells transfer via intra-hepatic artery, cetuximab and a high-dose IL-2 is feasible, well tolerated and may result in clinical responses.

Author Info: (1) University Bourgogne Franche-Comte, INSERM, EFS BFC, UMR1098, Interactions Hote-Greffon-Tumeur/Ingenierie Cellulaire et Genique, F-25000 Besancon, France. University Hospital of Besancon, Department of Medical Oncology, F-2500

Author Info: (1) University Bourgogne Franche-Comte, INSERM, EFS BFC, UMR1098, Interactions Hote-Greffon-Tumeur/Ingenierie Cellulaire et Genique, F-25000 Besancon, France. University Hospital of Besancon, Department of Medical Oncology, F-25000 Besancon, France. (2) University Bourgogne Franche-Comte, INSERM, EFS BFC, UMR1098, Interactions Hote-Greffon-Tumeur/Ingenierie Cellulaire et Genique, F-25000 Besancon, France. (3) University Bourgogne Franche-Comte, INSERM, EFS BFC, UMR1098, Interactions Hote-Greffon-Tumeur/Ingenierie Cellulaire et Genique, F-25000 Besancon, France. (4) University Hospital of Besancon, Department of Gastrointestinal and liver surgery, F-25000 Besancon, France. (5) University Bourgogne Franche-Comte, INSERM, EFS BFC, UMR1098, Interactions Hote-Greffon-Tumeur/Ingenierie Cellulaire et Genique, F-25000 Besancon, France. (6) University Bourgogne Franche-Comte, INSERM, EFS BFC, UMR1098, Interactions Hote-Greffon-Tumeur/Ingenierie Cellulaire et Genique, F-25000 Besancon, France. (7) University Bourgogne Franche-Comte, INSERM, EFS BFC, UMR1098, Interactions Hote-Greffon-Tumeur/Ingenierie Cellulaire et Genique, F-25000 Besancon, France. University Hospital of Besancon, Department of Medical Oncology, F-25000 Besancon, France. (8) University Bourgogne Franche-Comte, INSERM, EFS BFC, UMR1098, Interactions Hote-Greffon-Tumeur/Ingenierie Cellulaire et Genique, F-25000 Besancon, France. (9) University Bourgogne Franche-Comte, INSERM, EFS BFC, UMR1098, Interactions Hote-Greffon-Tumeur/Ingenierie Cellulaire et Genique, F-25000 Besancon, France. Etablissement Francais du Sang Bourgogne Franche-Comte, plateforme de BioMonitoring, F-25000 Besancon, France. INSERM CIC-1431, University Hospital of Besancon, Clinical Investigation Center in Biotherapy, F-25000, Besancon, France. (10) University Hospital of Besancon, Department of Medical Oncology, F-25000 Besancon, France. (11) Etablissement Francais du Sang Bourgogne Franche-Comte, F-25000 Besancon, France. (12) Etablissement Francais du Sang Bourgogne Franche-Comte, F-25000 Besancon, France. (13) Etablissement Francais du Sang Bourgogne Franche-Comte, F-25000 Besancon, France. (14) University Hospital of Besancon, Department of Gastroenterology, F-25000 Besancon, France. (15) University Bourgogne Franche-Comte, INSERM, EFS BFC, UMR1098, Interactions Hote-Greffon-Tumeur/Ingenierie Cellulaire et Genique, F-25000 Besancon, France. (16) University Bourgogne Franche-Comte, INSERM, EFS BFC, UMR1098, Interactions Hote-Greffon-Tumeur/Ingenierie Cellulaire et Genique, F-25000 Besancon, France. University Hospital of Besancon, Department of Medical Oncology, F-25000 Besancon, France. (17) University Bourgogne Franche-Comte, INSERM, EFS BFC, UMR1098, Interactions Hote-Greffon-Tumeur/Ingenierie Cellulaire et Genique, F-25000 Besancon, France. University Hospital of Besancon, Department of Pathology, F-25000 Besancon, France. (18) University Bourgogne Franche-Comte, INSERM, EFS BFC, UMR1098, Interactions Hote-Greffon-Tumeur/Ingenierie Cellulaire et Genique, F-25000 Besancon, France. (19) Etablissement Francais du Sang Bourgogne Franche-Comte, F-25000 Besancon, France. (20) University Hospital of Besancon, Department of Radiology, F-25000, Besancon, France. (21) University Bourgogne Franche-Comte, INSERM, EFS BFC, UMR1098, Interactions Hote-Greffon-Tumeur/Ingenierie Cellulaire et Genique, F-25000 Besancon, France. University Hospital of Besancon, Department of Medical Oncology, F-25000 Besancon, France.

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Checkpoints and beyond - Immunotherapy in colorectal cancer

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Immunotherapy is the latest revolution in cancer therapy. It continues to show impressive results in malignancies like melanoma and others. At least so far, effects are modest in colorectal cancer (CRC) and only a subset of patients benefits from already approved checkpoint inhibitors. In this review, we discuss major hurdles of immunotherapy like the immunosuppressive niche and low immunogenicity of CRC next to current achievements of checkpoint inhibitors, interleukin treatment and adoptive cell transfer (dendritic cells/cytokine induced killer cells, tumor infiltrating lymphocytes, chimeric antigen receptor cells, T cell receptor transfer) in pre-clinical models and clinical trials. We intensively examine approaches to overcome low immunogenicity by combination of different therapies and address future strategies of therapy as well as the need of predictive factors in this emerging field of precision medicine.

Author Info: (1) Department of Medicine II, Universitatsmedizin Mannheim, Medical Faculty Mannheim, University Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. (2) Department of Medicine II, Universitatsmedizin Mannheim, Medical

Author Info: (1) Department of Medicine II, Universitatsmedizin Mannheim, Medical Faculty Mannheim, University Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. (2) Department of Medicine II, Universitatsmedizin Mannheim, Medical Faculty Mannheim, University Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. (3) Department of Medicine II, Universitatsmedizin Mannheim, Medical Faculty Mannheim, University Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; Heilig-Geist Hospital Bensheim, Rodensteinstrasse 94, 64625 Bensheim, Germany. (4) Department of Medicine II, Universitatsmedizin Mannheim, Medical Faculty Mannheim, University Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. Electronic address: matthias.ebert@umm.de.

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IL-21 Increases the Reactivity of Allogeneic Human Vgamma9Vdelta2 T Cells Against Primary Glioblastoma Tumors

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Glioblastoma multiforme (GBM) remains the most frequent and deadliest primary brain tumor in adults despite aggressive treatments, because of the persistence of infiltrative and resistant tumor cells. Nonalloreactive human Vgamma9Vdelta2 T lymphocytes, the major peripheral gammadelta T-cell subset in adults, represent attractive effectors for designing immunotherapeutic strategies to track and eliminate brain tumor cells, with limited side effects. We analyzed the effects of ex vivo sensitizations of Vgamma9Vdelta2 T cells by IL-21, a modulating cytokine, on their cytolytic reactivity. We first showed that primary human GBM-1 cells were naturally eliminated by allogeneic Vgamma9Vdelta2 T lymphocytes, through a perforin/granzyme-mediated cytotoxicity. IL-21 increased both intracellular granzyme B levels and cytotoxicity of allogeneic human Vgamma9Vdelta2 T lymphocytes in vitro. Importantly, IL-21-enhanced cytotoxicity was rapid, which supports the development of sensitization(s) of gammadelta T lymphocytes before adoptive transfer, a process that avoids any deleterious effect associated with direct administrations of IL-21. Finally, we showed, for the first time, that IL-21-sensitized allogeneic Vgamma9Vdelta2 T cells significantly eliminated GBM tumor cells that developed in the brain after orthotopic administrations in vivo. Altogether our observations pave the way for novel efficient stereotaxic immunotherapies in GBM patients by using IL-21-sensitized allogeneic human Vgamma9Vdelta2 T cells.

Author Info: (1) CRCINA, INSERM, CNRS, Universite d'Angers, Universite de Nantes. LabEx IGO "Immunotherapy, Graft, Oncology". (2) CRCINA, INSERM, CNRS, Universite d'Angers, Universite de Nantes. LabEx IGO

Author Info: (1) CRCINA, INSERM, CNRS, Universite d'Angers, Universite de Nantes. LabEx IGO "Immunotherapy, Graft, Oncology". (2) CRCINA, INSERM, CNRS, Universite d'Angers, Universite de Nantes. LabEx IGO "Immunotherapy, Graft, Oncology". (3) CRCINA, INSERM, CNRS, Universite d'Angers, Universite de Nantes. LabEx IGO "Immunotherapy, Graft, Oncology". Hotel Dieu, Hopital de Nantes, Nantes, France. (4) CRCINA, INSERM, CNRS, Universite d'Angers, Universite de Nantes. LabEx IGO "Immunotherapy, Graft, Oncology". (5) CRCINA, INSERM, CNRS, Universite d'Angers, Universite de Nantes. LabEx IGO "Immunotherapy, Graft, Oncology". (6) CRCINA, INSERM, CNRS, Universite d'Angers, Universite de Nantes. LabEx IGO "Immunotherapy, Graft, Oncology". (7) CRCINA, INSERM, CNRS, Universite d'Angers, Universite de Nantes. LabEx IGO "Immunotherapy, Graft, Oncology".

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Natural Killer cells and their therapeutic role in pancreatic cancer: A systematic review

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Pancreatic cancer is among the three deadliest cancers worldwide with the lowest 5-year survival of all cancers. Despite all efforts, therapeutic improvements have barely been made over the last decade. Even recent highly promising targeted and immunotherapeutic approaches did not live up to their expectations. Therefore, other horizons have to be explored. Natural Killer (NK) cells are gaining more and more interest as a highly attractive target for cancer immunotherapies, both as pharmaceutical target and for cell therapies. In this systematic review we summarise the pathophysiological adaptions of NK cells in pancreatic cancer and highlight possible (future) therapeutic NK cell-related targets. Furthermore, an extensive overview of recent therapeutic approaches with an effect on NK cells is given, including cytokine-based, viro- and bacteriotherapy and cell therapy. We also discuss ongoing clinical trials that might influence NK cells. In conclusion, although several issues regarding NK cells in pancreatic cancer remain unsolved and need further investigation, extensive evidence is already provided that support NK cell oriented approaches in pancreatic cancer.

Author Info: (1) Center for Oncological Research, University of Antwerp, Antwerp, Belgium; Cancer Immunotherapy and Immune Innovation Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia. Electronic address: jonas.vanaudenaerde@uantwerp.be

Author Info: (1) Center for Oncological Research, University of Antwerp, Antwerp, Belgium; Cancer Immunotherapy and Immune Innovation Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia. Electronic address: jonas.vanaudenaerde@uantwerp.be. (2) Dept of Hepatobiliary, Endocrine and Transplantation Surgery, Antwerp University Hospital, Antwerp, Belgium. (3) Cancer Immunotherapy and Immune Innovation Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia. (4) Cancer Immunotherapy and Immune Innovation Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia. (5) Center for Oncological Research, University of Antwerp, Antwerp, Belgium; Dept of Oncology and Multidisciplinary Oncological Centre Antwerp, Antwerp University Hospital, Antwerp, Belgium. (6) Center for Oncological Research, University of Antwerp, Antwerp, Belgium; Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Antwerp, Belgium.

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Personalized cancer vaccine effectively mobilizes antitumor T cell immunity in ovarian cancer

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A pilot clinical study of a new whole-cell tumor lysate dendritic cell vaccine showed that in addition to being well-tolerated, the vaccine induced a tumor antigen-specific and neoantigen-specific antitumor immune response in some patients with ovarian cancer. Patients who responded to therapy showed remission inversion and improved progression-free and overall survival. Patients who received the vaccine in combination with bevacizumab and pretreatment with cyclophosphamide were most likely to immunologically respond and benefit.

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A pilot clinical study of a new whole-cell tumor lysate dendritic cell vaccine showed that in addition to being well-tolerated, the vaccine induced a tumor antigen-specific and neoantigen-specific antitumor immune response in some patients with ovarian cancer. Patients who responded to therapy showed remission inversion and improved progression-free and overall survival. Patients who received the vaccine in combination with bevacizumab and pretreatment with cyclophosphamide were most likely to immunologically respond and benefit.

We conducted a pilot clinical trial testing a personalized vaccine generated by autologous dendritic cells (DCs) pulsed with oxidized autologous whole-tumor cell lysate (OCDC), which was injected intranodally in platinum-treated, immunotherapy-naive, recurrent ovarian cancer patients. OCDC was administered alone (cohort 1, n = 5), in combination with bevacizumab (cohort 2, n = 10), or bevacizumab plus low-dose intravenous cyclophosphamide (cohort 3, n = 10) until disease progression or vaccine exhaustion. A total of 392 vaccine doses were administered without serious adverse events. Vaccination induced T cell responses to autologous tumor antigen, which were associated with significantly prolonged survival. Vaccination also amplified T cell responses against mutated neoepitopes derived from nonsynonymous somatic tumor mutations, and this included priming of T cells against previously unrecognized neoepitopes, as well as novel T cell clones of markedly higher avidity against previously recognized neoepitopes. We conclude that the use of oxidized whole-tumor lysate DC vaccine is safe and effective in eliciting a broad antitumor immunity, including private neoantigens, and warrants further clinical testing.

Author Info: (1) Ovarian Cancer Research Center, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Department of Oncology, Lausanne University

Author Info: (1) Ovarian Cancer Research Center, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. (3) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. (4) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. (5) Ovarian Cancer Research Center, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (6) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. (7) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. (8) Swiss Institute of Bioinformatics, Lausanne CH-1015, Switzerland. (9) Swiss Institute of Bioinformatics, Lausanne CH-1015, Switzerland. (10) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. (11) Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (12) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. (13) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. Swiss Institute of Bioinformatics, Lausanne CH-1015, Switzerland. (14) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. (15) Swiss Institute of Bioinformatics, Lausanne CH-1015, Switzerland. (16) Ovarian Cancer Research Center, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (17) Immunogenetics Laboratory, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (18) Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA. (19) Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA. (20) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. Swiss Institute of Bioinformatics, Lausanne CH-1015, Switzerland. (21) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. (22) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. (23) Ovarian Cancer Research Center, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (24) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. Swiss Institute of Bioinformatics, Lausanne CH-1015, Switzerland. (25) Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (26) Laboratory of Biostatistics, School of Health Sciences, National and Kapodistrian, University of Athens, Athens, Greece. (27) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. Swiss Institute of Bioinformatics, Lausanne CH-1015, Switzerland. (28) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. (29) Ovarian Cancer Research Center, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. (30) Ovarian Cancer Research Center, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. lana.kandalaft@chuv.ch. Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland.

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Dendritic Cell-Based Immunotherapy for Solid Tumors

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As a treatment for solid tumors, dendritic cell (DC)-based immunotherapy has not been as effective as expected. Here, we review the reasons underlying the limitations of DC-based immunotherapy for solid tumors and ask what can be done to improve immune cell-based cancer therapies. Several reports show that, rather than a lack of immune induction, the limited efficacy of DC-based immunotherapy in cases of renal cell carcinoma (RCC) likely results from inhibition of immune responses by tumor-secreted TGF-beta and an increase in the number of regulatory T (Treg) cells in and around the solid tumor. Indeed, unlike DC therapy for solid tumors, cytotoxic T lymphocyte (CTL) responses induced by DC therapy inhibit tumor recurrence after surgery; CTL responses also limit tumor metastasis induced by additional tumor-challenge in RCC tumor-bearing mice. Here, we discuss the mechanisms underlying the poor efficacy of DC-based therapy for solid tumors and stress the need for new and improved DC immunotherapies and/or combination therapies with killer cells to treat resistant solid tumors.

Author Info: (1) Department of Biotechnology, CHA University, Seongnam, Gyeonggi-do 13488, Republic of Korea; Pharos Vaccine Inc., Seongnam, Gyeonggi-do 13215, Republic of Korea. (2) Department of Biotechnology

Author Info: (1) Department of Biotechnology, CHA University, Seongnam, Gyeonggi-do 13488, Republic of Korea; Pharos Vaccine Inc., Seongnam, Gyeonggi-do 13215, Republic of Korea. (2) Department of Biotechnology, CHA University, Seongnam, Gyeonggi-do 13488, Republic of Korea; Pharos Vaccine Inc., Seongnam, Gyeonggi-do 13215, Republic of Korea. (3) Department of Biotechnology, CHA University, Seongnam, Gyeonggi-do 13488, Republic of Korea. (4) Department of Physical Education, Dong-Eui University, College of Arts and Sports Science, Busan 47340, Republic of Korea. (5) Department of Biotechnology, CHA University, Seongnam, Gyeonggi-do 13488, Republic of Korea. Electronic address: dslim@cha.ac.kr.

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WT1-pulsed Dendritic Cell Vaccine Combined with Chemotherapy for Resected Pancreatic Cancer in a Phase I Study

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BACKGROUND/AIM: Wilms' tumor 1 (WT1) is a tumor-associated antigen highly expressed in cancer. We examined the safety of WT1-peptide pulsed dendritic cell (WT1-DC) vaccine in combination with chemotherapy in patients with surgically resected pancreatic cancer. PATIENTS AND METHODS: Eight patients with resectable pancreatic cancer undergoing surgery either combined with S-1 or S-1 plus gemcitabine therapy were enrolled. Immunohistochemical analysis of WT1 was performed in 34 cases of pancreatic cancer. RESULTS: No serious side-effects were observed, except grade I fever in five and grade I reactions at the injection site in all patients. WT1-specific cytotoxic T-lymphocytes were detected in seven patients, and WT1 and human leukocyte antigen class I antigens were positive in all 34 cases. CONCLUSION: Our study clarified the safety and potential acquisition of immunity after vaccination targeting WT1. Further efficacy of WT1-DC vaccine to improve prognosis would be determined by a prospective clinical trial for resectable pancreatic cancer.

Author Info: (1) Center for Advanced Cell Therapy, Shinshu University Hospital, Matsumoto, Japan ryu@shinshu-u.ac.jp. (2) Shinshu Cancer Center, Shinshu University Hospital, Matsumoto, Japan. (3) Department of Regenerative

Author Info: (1) Center for Advanced Cell Therapy, Shinshu University Hospital, Matsumoto, Japan ryu@shinshu-u.ac.jp. (2) Shinshu Cancer Center, Shinshu University Hospital, Matsumoto, Japan. (3) Department of Regenerative Medicine, Kanazawa Medical University, Ishikawa, Japan. (4) Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan. (5) Department of Gastroenterology and Hepatology, The Jikei University School of Medicine, Kashiwa, Japan. (6) Transfusion and Cell Therapy Unit, Nagasaki University Hospital, Sakamoto, Japan. (7) Department of Advanced Immunotherapeutics, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Japan. (8) Department of Advanced Immunotherapeutics, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Japan. (9) Department of Functional Diagnostic Science, Graduate School of Medicine, Osaka University, Suita, Japan. (10) Department of Regenerative Medicine, Kanazawa Medical University, Ishikawa, Japan.

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