Journal Articles

Cellular immunotherapy

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

Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia (T-ALL)

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As a consequence of acquired or intrinsic disease resistance, the prognosis for patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) is dismal. Novel, less toxic drugs are clearly needed. One of the most promising emerging therapeutic strategies for cancer treatment is targeted immunotherapy. Immune therapies have improved outcomes for patients with other hematologic malignancies including B-ALL, however no immune therapy has been successfully developed for T-ALL. We hypothesize targeting CD38 will be effective against T-ALL. We demonstrate that blasts from patients with T-ALL have robust surface CD38 surface expression and that this expression remains stable after exposure to multi-agent chemotherapy. CD38 is expressed at very low levels on normal lymphoid and myeloid cells and on a few tissues of non-hematopoietic origin, suggesting that CD38 may be an ideal target. Daratumumab is a human IgG1kappa monoclonal antibody that binds CD38, and has been demonstrated to be safe and effective in patients with refractory multiple myeloma (MM). We tested daratumumab in a large panel of T-ALL patient-derived xenografts (PDX) and found striking efficacy in 14 of 15 different PDX. These data suggest that daratumumab is a promising novel therapy for pediatric T-ALL patients.

Author Info: (1) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University

Author Info: (1) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States. (2) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States. (3) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States. (4) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States. (5) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States. (6) Laura and Isaac Perlmutter Cancer Center at NYU Langone, New York University, New York, NY, United States. (7) Janssen Biotech, Horsham, PA, United States. (8) University of Florida, Gainesville, FL, United States. (9) University of Florida, Gainesville, FL, United States. (10) Carilion Children's Clinic, Roanoke, VA, United States. (11) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States. (12) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States. (13) Baylor College of Medicine Dan L Duncan Comprehensive Cancer Center, Houston, TX, United States. (14) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States. (15) Division of Hematology/Oncology, University of California San Francisco Benioff Children's Hospital, San Francisco, CA, United States. (16) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States. (17) Department of Pediatrics and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States. (18) Children's Minnesota Cancer and Blood Disorders, Minneapolis, MN, United States. (19) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States. (20) Division of Hematology/Oncology, University of California San Francisco Benioff Children's Hospital, San Francisco, CA, United States. (21) Seattle Children's Hospital, Seattle, WA, United States. (22) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States; teacheyd@email.chop.edu.

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Langerhans-type dendritic cells electroporated with TRP-2 mRNA stimulate cellular immunity against melanoma: Results of a phase I vaccine trial

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Purpose: We conducted a phase I vaccine trial to determine safety, toxicity, and immunogenicity of autologous Langerhans-type dendritic cells (LCs), electroporated with murine tyrosinase-related peptide-2 (mTRP2) mRNA in patients with resected AJCC stage IIB, IIC, III, or IV (MIa) melanoma. Experimental Design: Nine patients received a priming immunization plus four boosters at three week intervals. Vaccines comprised 10 x 10(6) mRNA-electroporated LCs, based on absolute number of CD83(+)CD86(bright)HLA-DR(bright)CD14(neg) LCs by flow cytometry. Initial vaccines used freshly generated LCs, whereas booster vaccines used viably thawed cells from the cryopreserved initial product. Post-vaccination assessments included evaluation of delayed-type hypersensitivity (DTH) reactions after booster vaccines and immune response assays at one and three months after the final vaccine. Results: All patients developed mild DTH reactions at injection sites after booster vaccines, but there were no toxicities exceeding grade 1 (CTCAE, v4.0). At one and three months post-vaccination, antigen-specific CD4 and CD8 T cells increased secretion of proinflammatory cytokines (IFN-gamma, IL-2, and TNF-alpha), above pre-vaccine levels, and also upregulated the cytotoxicity marker CD107a. Next-generation deep sequencing of the TCR-V-beta CDR3 documented fold-increases in clonality of 2.11 (range 0.85-3.22) for CD4 and 2.94 (range 0.98-9.57) for CD8 T cells at one month post-vaccines. Subset analyses showed overall lower fold-increases in clonality in three patients who relapsed (CD4: 1.83, CD8: 1.54) versus non-relapsed patients (CD4: 2.31, CD8: 3.99). Conclusions: TRP2 mRNA-electroporated LC vaccines are safe and immunogenic. Responses are antigen-specific in terms of cytokine secretion, cytolytic degranulation, and increased TCR clonality, which correlates with clinical outcomes.

Author Info: (1) Laboratory of Cellular Immunobiology, Memorial Sloan Kettering Cancer Center, New York, NY. Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York

Author Info: (1) Laboratory of Cellular Immunobiology, Memorial Sloan Kettering Cancer Center, New York, NY. Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY. Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Memorial Sloan Kettering Cancer Center, New York, NY. The Rockefeller University, New York, NY. Weill Cornell Medical College, New York, NY, USA. (2) Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, NY. Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Memorial Sloan Kettering Cancer Center, New York, NY. Weill Cornell Medical College, New York, NY, USA. (3) Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, NY. Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Memorial Sloan Kettering Cancer Center, New York, NY. Weill Cornell Medical College, New York, NY, USA. (4) Laboratory of Cellular Immunobiology, Memorial Sloan Kettering Cancer Center, New York, NY. Memorial Sloan Kettering Cancer Center, New York, NY. (5) Laboratory of Cellular Immunobiology, Memorial Sloan Kettering Cancer Center, New York, NY. Memorial Sloan Kettering Cancer Center, New York, NY. (6) Laboratory of Cellular Immunobiology, Memorial Sloan Kettering Cancer Center, New York, NY. Memorial Sloan Kettering Cancer Center, New York, NY. (7) Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, NY. Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Memorial Sloan Kettering Cancer Center, New York, NY. (8) Sarcoma Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY. Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Memorial Sloan Kettering Cancer Center, New York, NY. Weill Cornell Medical College, New York, NY, USA. (9) Sarcoma Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY. Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Memorial Sloan Kettering Cancer Center, New York, NY. Weill Cornell Medical College, New York, NY, USA. (10) Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, NY. Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Memorial Sloan Kettering Cancer Center, New York, NY. The Rockefeller University, New York, NY. Weill Cornell Medical College, New York, NY, USA. (11) Laboratory of Cellular Immunobiology, Memorial Sloan Kettering Cancer Center, New York, NY. Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY. Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Immunology Program, Sloan Kettering Institute for Cancer Research. Memorial Sloan Kettering Cancer Center, New York, NY. The Rockefeller University, New York, NY. Weill Cornell Medical College, New York, NY, USA.

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EpCAM peptide-primed dendritic cell vaccination confers significant anti-tumor immunity in hepatocellular carcinoma cells

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Cancer stem-like cells (CSCs) may play a key role in tumor initiation, self-renewal, differentiation, and resistance to current treatments. Dendritic cells (DCs) play a vital role in host immune reactions as well as antigen presentation. In this study, we explored the suitability of using CSC peptides as antigen sources for DC vaccination against human breast cancer and hepatocellular carcinoma (HCC) with the aim of achieving CSC targeting and enhancing anti-tumor immunity. CD44 is used as a CSC marker for breast cancer and EpCAM is used as a CSC marker for HCC. We selected CD44 and EpCAM peptides that bind to HLA-A2 molecules on the basis of their binding affinity, as determined by a peptide-T2 binding assay. Our data showed that CSCs express high levels of tumor-associated antigens (TAAs) as well as major histocompatibility complex (MHC) molecules. Pulsing DCs with CD44 and EpCAM peptides resulted in the efficient generation of mature DCs (mDCs), thus enhancing T cell stimulation and generating potent cytotoxic T lymphocytes (CTLs). The activation of CSC peptide-specific immune responses by the DC vaccine in combination with standard chemotherapy may provide better clinical outcomes in advanced carcinomas.

Author Info: (1) Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan, Republic of Korea. (2) Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan

Author Info: (1) Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan, Republic of Korea. (2) Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan, Republic of Korea. (3) Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan, Republic of Korea. (4) Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan, Republic of Korea. (5) Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan, Republic of Korea. Department of Radiation Oncology, Dongnam Institute of Radiological & Medical Sciences, Busan, Republic of Korea. Department of Radiation Oncology, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea. (6) Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan, Republic of Korea.

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Cancer immunotherapy in a neglected population: The current use and future of T-cell-mediated checkpoint inhibitors in organ transplant patients

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Although the indications for immune checkpoint inhibitors continue to grow, organ transplant recipients with advanced malignancies have been largely excluded from clinical trials testing the safety and efficacy of these therapies given their need for chronic immunosuppression and the risk of allograft rejection. With the rapid growth of transplant medicine and the increased risk of malignancy associated with chronic immunosuppression, it is critical that we systematically analyze the available data describing immune checkpoint blockade in the organ transplant population. Herein we provide a current and comprehensive review of cases in which immune checkpoint blockade was used on organ transplant recipients. Furthermore, we discuss the differences in efficacy and risk of allograft rejection between CTLA-4 and PD-1 inhibitors and make recommendations based on the limited available clinical data. We also discuss the future of immune checkpoint blockade in this subpopulation and explore the emerging data of promising combination therapies with mTOR, BRAF/MEK, and BTK/ITK inhibitors. Further clinical experience and larger clinical trials involving immune checkpoint inhibitors, whether as monotherapies or combinatorial therapies, will help develop regimens that optimize anti-tumor response and minimize the risk of allograft rejection in organ transplant patients.

Author Info: (1) Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA

Author Info: (1) Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA. Electronic address: young.chae@northwestern.edu. (2) Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. (3) Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. (4) Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. (5) Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

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Recent Successes and Future Directions in Immunotherapy of Cutaneous Melanoma

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The global health burden associated with melanoma continues to increase while treatment options for metastatic melanoma are limited. Nevertheless, in the past decade, the field of cancer immunotherapy has witnessed remarkable advances for the treatment of a number of malignancies including metastatic melanoma. Although the earliest observations of an immunological antitumor response were made nearly a century ago, it was only in the past 30 years, that immunotherapy emerged as a viable therapeutic option, in particular for cutaneous melanoma. As such, melanoma remains the focus of various preclinical and clinical studies to understand the immunobiology of cancer and to test various tumor immunotherapies. Here, we review key recent developments in the field of immune-mediated therapy of melanoma. Our primary focus is on therapies that have received regulatory approval. Thus, a brief overview of the pathophysiology of melanoma is provided. The purported functions of various tumor-infiltrating immune cell subsets are described, in particular the recently described roles of intratumoral dendritic cells. The section on immunotherapies focuses on strategies that have proved to be the most clinically successful such as immune checkpoint blockade. Prospects for novel therapeutics and the potential for combinatorial approaches are delineated. Finally, we briefly discuss nanotechnology-based platforms which can in theory, activate multiple arms of immune system to fight cancer. The promising advances in the field of immunotherapy signal the dawn of a new era in cancer treatment and warrant further investigation to understand the opportunities and barriers for future progress.

Author Info: (1) Institute of Pathology, Experimental Pathology, University of Bern, Bern, Switzerland. (2) Institute of Pathology, Experimental Pathology, University of Bern, Bern, Switzerland. (3) Department of

Author Info: (1) Institute of Pathology, Experimental Pathology, University of Bern, Bern, Switzerland. (2) Institute of Pathology, Experimental Pathology, University of Bern, Bern, Switzerland. (3) Department of Dermatology, University Hospital Bern, Bern, Switzerland. (4) Institute of Pathology, Experimental Pathology, University of Bern, Bern, Switzerland.

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Phase I clinical trial of a novel autologous modified-DC vaccine in patients with resected NSCLC

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BACKGROUND: The primary aim of this study was to evaluate the safety of a novel dendritic cell (DC) vaccine pulsed with survivin and MUC1, silenced with suppressor of cytokine signaling 1 (SOCS1), and immune stimulated with flagellin for patients with stage I to IIIA non-small cell lung cancer (NSCLC) in a phase I open-label, uncontrolled, and dose-escalation trial. Moreover, we evaluate the potential efficacy of this modified DC vaccine as secondary aim. METHODS: The patients were treated with the vaccine at 1 x 10(6), 1 x 10(7)and the maximum dose 8 x 10(7) at day 7, 14, and 21 after characterization of the vaccine phenotype by flow cytometry. The safety of the vaccine was assessed by adverse events, and the efficacy by the levels of several specific tumor markers and the patient quality of life. RESULTS: The vaccine was well tolerated without dose-limiting toxicity even at higher doses. The most common adverse event reported was just grade 1 flu-like symptoms without unanticipated or serious adverse event. A significant decrease in CD3 + CD4 + CD25 + Foxp3+ T regulatory (Treg) cell number and increase in TNF-alpha and IL-6 were observed in two patients. Two patients showed 15% and 64% decrease in carcino-embryonic antigen and CYFRA21, respectively. The vaccination with the maximum dose significantly improved the patients'quality of life when administered at the highest dose. More importantly, in the long-term follow-up until February 17, 2017, 1 patient had no recurrence, 1 patients had a progressive disease (PD), and 1 patient was died in the low dose group. In the middle dose group, all 3 patients had no recurrence. In the high dose group, 1 patient was died, 1 patient had a PD, and the other 7 patients had no recurrence. CONCLUSIONS: We provide preliminary data on the safety and efficacy profile of a novel vaccine against non-small cell lung cancer, which was reasonably well tolerated, induced modest antitumor activity without dose-limiting toxicity, and improved patients' quality of life. Further more, the vaccine maybe a very efficacious treatment for patients with resected NSCLC to prevent recurrence. Our findings on the safety and efficacy of the vaccine in this phase I trial warrant future phase II/III clinical trial.

Author Info: (1) Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, 650118, China. (2) Cancer Biotherapy Center

Author Info: (1) Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, 650118, China. (2) Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, 650118, China. (3) Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, 650118, China. (4) Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, 650118, China. (5) Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, 650118, China. (6) Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, 650118, China. (7) Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, 650118, China. (8) Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, 650118, China. (9) Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, 650118, China. (10) Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, 650118, China. (11) Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, 650118, China. (12) Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, 650118, China. (13) Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, 650118, China. (14) Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, 650118, China. (15) Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, 650118, China. (16) Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA. siyichen@usc.edu. Department of Immunology, Baylor College of Medicine, Houston, TX, USA. siyichen@usc.edu. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. siyichen@usc.edu. (17) Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, 650118, China. songxin68@126.com.

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Establishment of Synergistic Chemoimmunotherapy for Head and Neck Cancer Using Peritumoral Immature Dendritic Cell Injections and Low-Dose Chemotherapies

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The lack of available tumor antigens with strong immunogenicity, human leukocyte antigen restriction, and immunosuppression via regulatory T-cells (Tregs) and myeloid-derived suppressor cells are limitations for dendritic cell (DC)-based immunotherapy in patients with advanced head and neck cancer (HNC). We sought to overcome these limitations and induce effective antitumor immunity in the host. The effect of low-dose docetaxel (DTX) treatment on DC maturation was examined in an ex vivo study, and a phase I clinical trial of combination therapy with direct peritumoral immature DC (iDC) injection with OK-432 and low-dose cyclophosphamide (CTX) plus DTX was designed. Low-dose DTX did not negatively affect iDC viability and instead promoted maturation and IL-12 production. Five patients with metastatic or recurrent HNC were enrolled for the trial. All patients experienced grade 1 to 3 fevers. Intriguingly, elevated CD8+ effector T-cells and reduced Tregs were observed in four patients who completed two treatment cycles. All patients were judged to have progressive disease, but tumor regressions were observed in a subset of targeted metastatic lesions in two of five patients. Our results show that the combination of direct peritumoral iDC injection with OK-432 and low-dose CTX plus DTX is well tolerated and should give rise to changing the immune profile of T-cell subsets and improvement of immunosuppression in advanced HNC patients. Additionally, our ex vivo data on the effect of low-dose DTX treatment on DC maturation may contribute to developing new combination therapies with low-dose chemotherapy and immunotherapy.

Author Info: (1) Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi. Electronic address: ishiih@yamanashi.ac.jp. (2) Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi

Author Info: (1) Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi. Electronic address: ishiih@yamanashi.ac.jp. (2) Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi; Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine. (3) Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi. (4) Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine. (5) Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi. (6) Division of Transfusion Medicine and Cell Therapy, University of Yamanashi Hospital. (7) Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi. (8) Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi. (9) Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi. Electronic address: mkeisuke@yamanashi.ac.jp.

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Sipuleucel-T for the treatment of prostate cancer: novel insights and future directions

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Sipuleucel-T, an autologous cellular immunotherapy manufactured from antigen-presenting cells primed to recognize prostatic acid phosphatase, was the first immunotherapy product approved by the US FDA. It was approved for men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer after it was shown to provide a survival advantage. Additional studies have examined its use in other clinical settings and in combination with other approved and investigational immunotherapy agents. This review will discuss the pivotal trials leading to approval, will outline some of the biomarkers associated with its efficacy and will review some of the ongoing combination strategies. Maximizing the efficacy of sipuleucel-T through better patient selection or through combination approaches remains the challenge of the future.

Author Info: (1) Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, MD 21287, USA. (2) Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, MD 21287, USA.

Author Info: (1) Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, MD 21287, USA. (2) Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, MD 21287, USA.

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Radiotherapy enhances natural killer cell cytotoxicity and localization in pre-clinical canine sarcomas and first-in-dog clinical trial

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BACKGROUND: We have previously shown that radiotherapy (RT) augments natural killer (NK) functions in pre-clinical models of human and mouse cancers, including sarcomas. Since dogs are an excellent outbred model for immunotherapy studies, we sought to assess RT plus local autologous NK transfer in canine sarcomas. METHODS: Dog NK cells (CD5(dim), NKp46+) were isolated from PBMCs and expanded with irradiated K562-C9-mIL21 feeder cells and 100 IU/mL recombinant human IL-2. NK homing and cytotoxicity +/- RT were evaluated using canine osteosarcoma tumor lines and dog patient-derived xenografts (PDX). In a first-in-dog clinical trial for spontaneous osteosarcoma, we evaluated RT and intra-tumoral autologous NK transfer. RESULTS: After 14 days, mean NK expansion and yield were 19.0-fold (+/-8.6) and 258.9(+/-76.1) x10(6) cells, respectively. Post-RT, NK cytotoxicity increased in a dose-dependent fashion in vitro reaching ~ 80% at effector:target ratios of >/=10:1 (P < 0.001). In dog PDX models, allogeneic NK cells were cytotoxic in ex vivo killing assays and produced significant PDX tumor growth delay (P < 0.01) in vivo. After focal RT and intravenous NK transfer, we also observed significantly increased NK homing to tumors in vivo. Of 10 dogs with spontaneous osteosarcoma treated with focal RT and autologous NK transfer, 5 remain metastasis-free at the 6-month primary endpoint with resolution of suspicious pulmonary nodules in one patient. We also observed increased activation of circulating NK cells after treatment and persistence of labelled NK cells in vivo. CONCLUSIONS: NK cell homing and cytotoxicity are increased following RT in canine models of sarcoma. Results from a first-in-dog clinical trial are promising, including possible abscopal effects.

Author Info: (1) Department of Surgery, Division of Surgical Oncology, University of California Davis Medical Center, Sacramento, CA, 95817, USA. rjcanter@ucdavis.edu. Department of Surgery, Division of Surgical

Author Info: (1) Department of Surgery, Division of Surgical Oncology, University of California Davis Medical Center, Sacramento, CA, 95817, USA. rjcanter@ucdavis.edu. Department of Surgery, Division of Surgical Oncology, UC Davis School of Medicine, 4501 X Street, Suite 3010, Sacramento, CA, 95817, USA. rjcanter@ucdavis.edu. (2) Laboratory of Cancer Immunology, Department of Dermatology, University of California Davis Medical Center, Sacramento, CA, 95817, USA. (3) Nationwide Children's Hospital, Center for Childhood Cancer & Blood Diseases, 700 Children's Drive, Columbus, OH, 43205, USA. (4) Laboratory of Cancer Immunology, Department of Dermatology, University of California Davis Medical Center, Sacramento, CA, 95817, USA. (5) Department of Surgery, University of California Davis Medical Center, Sacramento, CA, 95817, USA. (6) Laboratory of Cancer Immunology, Department of Dermatology, University of California Davis Medical Center, Sacramento, CA, 95817, USA. (7) The Center for Companion Animal Health, Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA, 95616, USA. (8) The Center for Companion Animal Health, Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA, 95616, USA. (9) Department of Pathology and Laboratory Medicine, UT Southwestern Medical Center, Dallas, TX, 75390, USA. (10) Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Animal Cancer Care and Research Center, Center for Immunology, Masonic Cancer Center, and Stem Cell Institute, University of Minnesota, St. Paul, MN, 55108, USA. (11) Department of Radiation Oncology, University of California Davis Medical Center, Sacramento, CA, 95817, USA. (12) Nationwide Children's Hospital, Center for Childhood Cancer & Blood Diseases, 700 Children's Drive, Columbus, OH, 43205, USA. (13) Departments of Dermatology and Internal Medicine, University of California Davis Medical Center, Sacramento, CA, 95817, USA.

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Immuno-Oncology in Hepatocellular Carcinoma: 2017 Update

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Clinical trials are currently ongoing to evaluate the utility of antibodies against programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) as monotherapy or combination therapy in patients with hepatocellular carcinoma (HCC). Results of combination treatment with the anti-PD-L1 antibody durvalumab and the anti-CTLA-4 antibody tremelimumab in HCC were presented at the 2017 annual meeting of the ASCO (American Society of Clinical Oncology). Response rates were 25% in all 40 patients and 40% in the 20 uninfected patients, both of which are encouraging. Transcatheter arterial chemoembolization and radiofrequency ablation can activate tumor immunogenicity by releasing tumor-associated antigen and by inducing the migration of cytotoxic T lymphocytes to small intrahepatic metastatic nodules. Subsequent administration of anti-PD-1 antibody could control these small intrahepatic metastatic nodules. In a nonclinical study, the combination of pembrolizumab and lenvatinib inhibited the cancer immunosuppressive environments induced by tumor-associated macrophages and regulatory T cells. This, in turn, decreased the levels of TGF-beta and IL-10, the expression of PD-1, and the inhibition of Tim-3, triggering anticancer immunity mediated by immunostimulatory cytokines such as IL-12. Studies such as these may provide insight into the appropriate molecular targeted agents to be used with immune checkpoint inhibitors.

Author Info: (1) Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.

Author Info: (1) Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.

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