Journal Articles

Experimental Immunotherapy

Preclinical and clinical cancer immunotherapy approaches

Development of Inducible CD19-CAR T Cells with a Tet-On System for Controlled Activity and Enhanced Clinical Safety

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The tetracycline regulatory system has been widely used to control the transgene expression. With this powerful tool, it might be possible to effectively control the functional activity of chimeric antigen receptor (CAR) T cells and manage the severe side effects after infusion. In this study, we developed novel inducible CD19CAR (iCAR19) T cells by incorporating a one-vector Tet-on system into the CD19CAR construct. The iCAR19 T cells showed dox-dependent cell proliferation, cytokine production, CAR expression, and strong CD19-specific cytotoxicity. After 48 h of dox induction, the relative CAR expression of induced cells was five times greater than that of uninduced cells. Twenty-four hours after dox removal, CAR expression significantly decreased by more than 60%. In cytotoxicity assays, dox-treated cells induced significantly higher specific lysis against target cells. These results suggested that the activity of iCAR19 T cells was successfully controlled by our Tet-on system, offering an enhanced safety profile while maintaining a robust anti-tumor effect. Besides, all manufacture processes of the lentiviral vectors and the T cells were conducted according to the Good Manufacturing Practice (GMP) standards for subsequent clinical translation.

Author Info: (1) International Research Center for Marine Biosciences at Shanghai Ocean University, Ministry of Science and Technology, Shanghai 201306, China. xingjian.gu@mavs.uta.edu. National Pathogen Collection Center for

Author Info: (1) International Research Center for Marine Biosciences at Shanghai Ocean University, Ministry of Science and Technology, Shanghai 201306, China. xingjian.gu@mavs.uta.edu. National Pathogen Collection Center for Aquatic Animals, Shanghai 201306, China. xingjian.gu@mavs.uta.edu. Shanghai Collaborative Innovation for Aquatic Animal Genetics and Breeding, Shanghai 201306, China. xingjian.gu@mavs.uta.edu. Shanghai Telebio Biomedical Co., Ltd., Shanghai 201321, China. xingjian.gu@mavs.uta.edu. (2) Shanghai Telebio Biomedical Co., Ltd., Shanghai 201321, China. hdy_telebio@163.com. (3) Shanghai Telebio Biomedical Co., Ltd., Shanghai 201321, China. cx-l824@163.com. (4) Shanghai Telebio Biomedical Co., Ltd., Shanghai 201321, China. vector.telebio@163.com. (5) International Research Center for Marine Biosciences at Shanghai Ocean University, Ministry of Science and Technology, Shanghai 201306, China. ghyang119@163.com. National Pathogen Collection Center for Aquatic Animals, Shanghai 201306, China. ghyang119@163.com. Shanghai Collaborative Innovation for Aquatic Animal Genetics and Breeding, Shanghai 201306, China. ghyang119@163.com. Shanghai Telebio Biomedical Co., Ltd., Shanghai 201321, China. ghyang119@163.com.

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Combining DNA vaccine and AIM2 in H1 nanoparticles exert anti-renal carcinoma effects via enhancing tumor-specific multi-functional CD8+ T cell responses

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Renal carcinoma presents a rapid progression in patients with high metastasis with no effective therapeutic strategy. In this study, we designed a folate grafted PEI600-CyD (H1) nanoparticle-mediated DNA vaccine containing an adjuvant of absent in melanoma 2 (AIM2) and a tumor-specific antigen of carbonic anhydrase IX (CAIX) for renal carcinoma therapy. Mice bearing subcutaneous human CAIX (hCAIX)-Renca tumor were intramuscularly immunized with H1-pAIM2/pCAIX, H1-pCAIX, H1-pAIM2, or Mock vaccine, respectively. The tumor growth of hCAIX-Renca was significantly inhibited in H1-pAIM2/pCAIX vaccine group compared with control group. The vaccine activated CAIX-specific CD8+ T cell proliferation and cytotoxic T lymphocyte (CTL) responses, and enhanced the induction of multi-functional CD8+ T cells (expressing TNF-alpha, IL-2, and IFN-gamma). CD8+ T cell depletion resulted in the loss of anti-tumor activity of H1-pAIM2/pCAIX vaccine, suggesting that the efficacy of the vaccine was dependent on CD8+ T cell responses. Lung metastasis of renal carcinoma was also suppressed by H1-pAIM2/pCAIX vaccine treatment accompanied with the increased percentages of CAIX-specific multi-functional CD8+ T cells in the spleen, tumor, and bronchoalveolar lavage as compared with H1-pCAIX vaccine. Similarly, the vaccine enhanced CAIX-specific CD8+ T cell proliferation and CTL responses. Therefore, these results indicated that H1-pAIM2/pCAIX vaccine exhibits the therapeutic efficacy of anti-renal carcinoma by enhancing tumor-specific multi-functional CD8+ T cell responses. This vaccine strategy could be a potential and promising approach for the therapy of primary solid or metastasis tumors.

Author Info: (1) Cancer Institute, Xuzhou Medical University. (2) Department of Orthopedics, Affiliated Hospital of Xuzhou Medical University. (3) Cancer Institute, Xuzhou Medical University. (4) Cancer Institute

Author Info: (1) Cancer Institute, Xuzhou Medical University. (2) Department of Orthopedics, Affiliated Hospital of Xuzhou Medical University. (3) Cancer Institute, Xuzhou Medical University. (4) Cancer Institute, Xuzhou Medical University. (5) Cancer Institute, Xuzhou Medical University. (6) Cancer Institute, Xuzhou Medical University. (7) Cancer Institute, Xuzhou Medical University. (8) Biology college, Hunan University. (9) Cancer Institute, Xuzhou Medical University. (10) Cancer Institute, Xuzhou Medical University. (11) Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University jnzheng@xzhmu.edu.cn.

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Clinical immunotherapeutic approaches for the treatment of head and neck cancer

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, accounting for more than 550,000 cases and 380,000 deaths annually. The primary risk factors associated with HNSCC are tobacco use and alcohol consumption; nevertheless genetic predisposition and oncogenic viruses also play important roles in the development of these malignancies. The current treatments for HNSCC patients include surgery, chemotherapy, radiotherapy, and cetuximab, and combinations of these. However, these treatments are associated with significant toxicity, and many patients are either refractory to the treatment or relapse after a short period. Despite improvements in the treatment of patients with HNSCC, the clinical outcomes of those who have been treated with standard therapies have remained unchanged for over three decades and the 5-year overall survival rate in these patients remains around 40-50%. Therefore, more specific and less toxic therapies are needed in order to improve patient outcomes. The tumour microenvironment of HNSCC is immunosuppressive; therefore immunotherapy strategies that can overcome the immunosuppressive environment and produce long-term tumour immunosurveillance will have a significant therapeutic impact in these patients. This review focuses on the current immunological treatment options under investigation or available for clinical use in patients with HNSCC.

Author Info: (1) Department of Molecular Oncology, King's College London, London, UK. (2) Department of Molecular Oncology, King's College London, London, UK. Electronic address: mahvash.tavassoli@kcl.ac.uk.

Author Info: (1) Department of Molecular Oncology, King's College London, London, UK. (2) Department of Molecular Oncology, King's College London, London, UK. Electronic address: mahvash.tavassoli@kcl.ac.uk.

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Phase 1 Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma

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NKG2D ligands are widely expressed in solid and hematologic malignancies but absent or poorly expressed on healthy tissues. We conducted a phase 1 dose-escalation study to evaluate the safety and feasibility of a single infusion of NKG2D-chimeric antigen receptor (CAR) T cells, without lymphodepleting conditioning in subjects with acute myeloid leukemia/myelodysplastic syndrome or relapsed/refractory multiple myeloma. Autologous T cells were transfected with a gamma-retroviral vector encoding a CAR fusing human NKG2D with the CD3zeta signaling domain. Four dose levels (1x10e6-3x10e7 total viable T cells) were evaluated. Twelve subjects were infused (7 AML, 5 MM). NKG2D-CAR products demonstrated a median 75% vector-driven NKG2D expression on CD3+ T cells. No dose-limiting toxicities, cytokine release syndrome, or CAR T cell-related neurotoxicity was observed. No significant autoimmune reactions were noted, and none of the >/= Grade 3 adverse events were attributable to NKG2D-CAR T cells. At the single injection of low cell doses employed in this trial, no objective tumor responses were observed. However, hematologic parameters transiently improved in one subject with AML at the highest dose, and cases of disease stability without further therapy or on subsequent treatments were noted. At 24 hours, the cytokine RANTES increased a median of 1.9-fold among all subjects and 5.8-fold among 6 AML patients. Consistent with preclinical studies, NKG2D-CAR T cell-expansion and persistence were limited. Manufactured NKG2D-CAR T cells exhibited functional activity against autologous tumor cells in vitro, but modifications to enhance CAR T-cell expansion and target density may be needed to boost clinical activity.

Author Info: (1) Division of Pediatric Oncology and Division of Hematologic Malignancies, Dana-Farber Cancer Institute. (2) Celdara Medical. (3) Biostatistics and Computational Biology, Dana-Farber Cancer Center. (4)

Author Info: (1) Division of Pediatric Oncology and Division of Hematologic Malignancies, Dana-Farber Cancer Institute. (2) Celdara Medical. (3) Biostatistics and Computational Biology, Dana-Farber Cancer Center. (4) Adult Oncology, Dana-Farber Cancer Institute. (5) Dana-Farber Cancer Institute. (6) Dana-Farber Cancer Institute. (7) Celdara Medical. (8) Administration, Celdara Medical. (9) Microbiology and Immunology, Geisel School of Medicine at Dartmouth. (10) R&D, Celyad SA. (11) Oncology, Celyad (Belgium). (12) Medical Oncology, Dana-Farber Cancer Institute. (13) Multiple Myeloma, Dana-Farber Cancer Institute. (14) Dana-Farber Cancer Institute. (15) Jerome Lipper Multiple Myeloma Center,Department of Medical Oncology, Dana-Farber Cancer Insitute. (16) Medical Oncology, Dana-Farber Cancer Institute. (17) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute. (18) Medical Oncology, Dana-Farber Cancer Institute. (19) Novartis Therapeutics. (20) Division of Hematologic Malignancies, Dana-Farber Cancer Institute. (21) Medical Oncology, Dana-Farber Cancer Institute sarah_nikiforow@dfci.harvard.edu.

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CD33/CD3-bispecific T-cell engaging (BiTE(R)) antibody construct targets monocytic AML myeloid-derived suppressor cells

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Acute myeloid leukemia (AML) is the most common acute leukemia amongst adults with a 5-year overall survival lower than 30%. Emerging evidence suggest that immune alterations favor leukemogenesis and/or AML relapse thereby negatively impacting disease outcome. Over the last years myeloid derived suppressor cells (MDSCs) have been gaining momentum in the field of cancer research. MDSCs are a heterogeneous cell population morphologically resembling either monocytes or granulocytes and sharing some key features including myeloid origin, aberrant (immature) phenotype, and immunosuppressive activity. Increasing evidence suggests that accumulating MDSCs are involved in hampering anti-tumor immune responses and immune-based therapies. Here, we demonstrate increased frequencies of CD14(+) monocytic MDSCs in newly diagnosed AML that co-express CD33 but lack HLA-DR (HLA-DR(lo)). AML-blasts induce HLA-DR(lo) cells from healthy donor-derived monocytes in vitro that suppress T-cells and express indoleamine-2,3-dioxygenase (IDO). We investigated whether a CD33/CD3-bispecific BiTE(R) antibody construct (AMG 330) with pre-clinical activity against AML-blasts by redirection of T-cells can eradicate CD33(+) MDSCs. In fact, T-cells eliminate IDO(+)CD33(+) MDSCs in the presence of AMG 330. Depletion of total CD14(+) cells (including MDSCs) in peripheral blood mononuclear cells from AML patients did not enhance AMG 330-triggered T-cell activation and expansion, but boosted AML-blast lysis. This finding was corroborated in experiments showing that adding MDSCs into co-cultures of T- and AML-cells reduced AML-blast killing, while IDO inhibition promotes AMG 330-mediated clearance of AML-blasts. Taken together, our results suggest that AMG 330 may achieve anti-leukemic efficacy not only through T-cell-mediated cytotoxicity against AML-blasts but also against CD33(+) MDSCs, suggesting that it is worth exploring the predictive role of MDSCs for responsiveness towards an AMG 330-based therapy.

Author Info: (1) Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Ulmenweg 18, 91054, Erlangen, Germany. (2) Department of Internal Medicine 5, Hematology and

Author Info: (1) Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Ulmenweg 18, 91054, Erlangen, Germany. (2) Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Ulmenweg 18, 91054, Erlangen, Germany. (3) Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Ulmenweg 18, 91054, Erlangen, Germany. (4) Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Ulmenweg 18, 91054, Erlangen, Germany. (5) Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Ulmenweg 18, 91054, Erlangen, Germany. (6) Amgen Research GmbH, Munich, Germany. (7) Amgen Research GmbH, Munich, Germany. (8) Clinical Biomarkers and Diagnostics, Amgen Inc., South San Francisco, CA, USA. (9) Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Ulmenweg 18, 91054, Erlangen, Germany. (10) Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Ulmenweg 18, 91054, Erlangen, Germany. dimitrios.mougiakakos@uk-erlangen.de.

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Time to abandon single-site irradiation for inducing abscopal effects

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Considerable interest is being directed toward combining immune-checkpoint inhibition (ICI) with radiotherapy to improve response rates to ICI, which have been disappointingly low at around 15-30% among patients with advanced-stage cancers other than melanoma. Since a case report published in 2012, in which authors described the resolution of metastatic disease after irradiation of a single lesion in a patient who had been receiving ICI, hundreds of clinical trials have been launched with the aim of testing the safety and/or efficacy of radiotherapy in combination with immunotherapy, nearly all of which use this single-site irradiation, or 'abscopal', approach. However, emerging preclinical and clinical evidence suggests that this approach likely produces suboptimal results. In this Perspective, we describe this evidence and provide a biological rationale supporting the abandonment of the single-site abscopal approach. We instead advocate exploring comprehensive irradiation of multiple/all lesions in order to enhance the likelihood of obtaining meaningful clinical outcomes - if such a clinical synergy between radiation and ICI does exist - before the failure of the current, single-site approach leads to the potential premature and inappropriate abandonment of radiotherapy in combination with ICI altogether.

Author Info: (1) Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Radiation Oncology, Unit 97

Author Info: (1) Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. jychang@mdanderson.org.

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Radiotherapy induces responses of lung cancer to CTLA-4 blockade

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Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in preclinical studies and in some patients with melanoma(1-3), but its efficacy in inducing systemic responses (abscopal responses) against tumors unresponsive to CTLA-4 blockade remained uncertain. Radiation therapy promotes the activation of anti-tumor T cells, an effect dependent on type I interferon induction in the irradiated tumor(4-6). The latter is essential for achieving abscopal responses in murine cancers(6). The mechanisms underlying abscopal responses in patients treated with radiation therapy and CTLA-4 blockade remain unclear. Here we report that radiation therapy and CTLA-4 blockade induced systemic anti-tumor T cells in chemo-refractory metastatic non-small-cell lung cancer (NSCLC), where anti-CTLA-4 antibodies had failed to demonstrate significant efficacy alone or in combination with chemotherapy(7,8). Objective responses were observed in 18% of enrolled patients, and 31% had disease control. Increased serum interferon-beta after radiation and early dynamic changes of blood T cell clones were the strongest response predictors, confirming preclinical mechanistic data. Functional analysis in one responding patient showed the rapid in vivo expansion of CD8 T cells recognizing a neoantigen encoded in a gene upregulated by radiation, supporting the hypothesis that one explanation for the abscopal response is radiation-induced exposure of immunogenic mutations to the immune system.

Author Info: (1) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. formenti@med.cornell.edu. (2) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA

Author Info: (1) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. formenti@med.cornell.edu. (2) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. (3) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. Department of Radiation Oncology, University of California, San Francisco, CA, USA. (4) Department of Radiation Oncology, New York University School of Medicine, New York, NY, USA. (5) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. (6) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. (7) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. (8) Department of Radiology, New York University School of Medicine, New York, NY, USA. (9) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA. (10) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA. (11) Department of Pathology, New York University School of Medicine, New York, NY, USA. Genome Technology Center, Division of Advanced research Technologies, NYU Langone Health, New York, NY, USA. (12) Tisch Cancer Institute, Hematology/Oncology, Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (13) Tisch Cancer Institute, Hematology/Oncology, Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (14) Adaptive Biotechnologies, Seattle, WA, USA. (15) Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY, USA. (16) Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA. (17) Department of Medicine, New York University School of Medicine, New York, NY, USA. (18) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. szd3005@med.cornell.edu. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. szd3005@med.cornell.edu.

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Cell surface Notch ligand DLL3 is a therapeutic target in isocitrate dehydrogenase mutant glioma

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PURPOSE: Isocitrate dehydrogenase (IDH) mutant gliomas are a distinct glioma molecular subtype for which no effective molecularly-directed therapy exists. Low-grade gliomas, which are 80-90% IDH mutant, have high RNA levels of the cell surface Notch ligand DLL3. We sought to determine DLL3 expression by immunohistochemistry in glioma molecular subtypes and the potential efficacy of an anti-DLL3 antibody drug conjugate (ADC), rovalpituzumab tesirine (Rova-T), in IDH mutant glioma. EXPERIMENTAL DESIGN: We evaluated DLL3 expression by RNA using TCGA data and by immunohistochemistry in a discovery set of 63 gliomas and 20 non-tumor brain tissues and a validation set of 62 known IDH wildtype and mutant gliomas using a monoclonal anti-DLL3 antibody. Genotype was determined using a DNA methylation array classifier or by sequencing. The effect of Rova-T on patient-derived endogenous IDH mutant glioma tumorspheres was determined by cell viability assay. RESULTS: Compared to IDH wildtype glioblastoma, IDH mutant gliomas have significantly higher DLL3 RNA (P<1x10-15) and protein by immunohistochemistry (P=0.0014 and P<4.3x10-6 in the discovery and validation set, respectively). DLL3 immunostaining was intense and homogeneous in IDH mutant gliomas, retained in all recurrent tumors, and detected in only 1 of 20 non-tumor brains. Patient-derived IDH mutant glioma tumorspheres overexpressed DLL3 and were potently sensitive to Rova-T in an antigen-dependent manner. CONCLUSIONS: DLL3 is selectively and homogeneously expressed in IDH mutant gliomas and can be targeted with Rova-T in patient-derived IDH mutant glioma tumorspheres. Our findings are potentially immediately translatable and have implications for therapeutic strategies that exploit cell surface tumor-associated antigens.

Author Info: (1) Pathology, NYU Langone Health. (2) Laura and Isaac Perlmutter Cancer Center, NYU Langone Health. (3) CBRD, New York University Langone Medical Center. (4) Pathology

Author Info: (1) Pathology, NYU Langone Health. (2) Laura and Isaac Perlmutter Cancer Center, NYU Langone Health. (3) CBRD, New York University Langone Medical Center. (4) Pathology, New York University Langone Medical Center and Medical School. (5) Pathology, NYU Langone Health. (6) Laura and Isaac Perlmutter Cancer Center, NYU Langone Health. (7) Pathology, NYU Langone Health. (8) Pathology, NYU Langone Health. (9) Pathology, NYU Langone Health. (10) Pathology, NYU Langone Medical Center. (11) Neurosurgery, NYU School of Medicine. (12) Neurosurgery, NYU Langone Health. (13) Neurosurgery, Yokohama City University. (14) Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School. (15) Department of Radiology, New York University Langone Medical Center. (16) Neurosurgery, NYU Langone Health. (17) NYU Langone Health. (18) Radiation Oncology, New York University Langone Medical Center. (19) Department of Neurosurgery, Massachusetts General Hospital / Harvard Medical School. (20) Department of Neurosurgery, New York University Langone Medical Center. (21) AbbVie Stemcentrx LLC. (22) Molecular Biology, Abbvie Stemcentrx. (23) Department of Pathology, Division of Neuropathology and Department of Neurosurgery, New York University School of Medicine. (24) Neurosurgery, NYU School of Medicine. (25) Pathology, NYU Langone Medical Center. (26) Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine chia01@nyumc.org.

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A Novel Combination Therapy for Human Oxaliplatin-resistant Colorectal Cancer Using Oxaliplatin and Coxsackievirus A11

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BACKGROUND: Colorectal cancer (CRC) is a major cause of morbidity and mortality throughout the world. It is the third most common cancer worldwide and the fourth most common cause of cancer-related death. FOLFOX, a combination of leucovorin calcium, fluorouracil, and oxaliplatin, is the first-line chemotherapy for stage III and stage IV CRC. However, patients with FOLFOX-resistant CRC have a poor prognosis. In recent years, virochemotherapy has been proposed as a potential treatment for chemotherapy-resistant cancer. MATERIALS AND METHODS: Through our first screening assay, we found that coxsackievirus A11 (CVA11) displayed potent oncolytic activities. We tested whether coxsackievirus A11 (CVA11) has oncolytic activity in human CRC cells in vitro and in vivo. We also examined whether pretreatment of oxaliplatin-resistant CRC cells with oxaliplatin enhances the oncolytic activity of CVA11. RESULTS: We found that CVA11 was potently oncolytic against the oxaliplatin-sensitive Caco-2 cell line, but had little effect on the oxaliplatin-resistant line WiDr. However, pretreatment of WiDr cells with oxaliplatin enhanced the oncolytic activity of CVA11, and the combination therapy was more cytotoxic than either oxaliplatin treatment or CVA11 infection alone. Furthermore, growth of subcutaneous WiDr tumors in a xenograft model was significantly lower in mice treated with oxaliplatin followed by intratumoral CVA11 injection compared with mice receiving either treatment alone. CONCLUSION: Oxaliplatin pretreatment sensitized oxaliplatin-resistant CRC cells to lysis by CVA11 infection in vitro and in vivo. Taken together, these findings identify a novel potential chemovirotherapeutic modality for the treatment of oxaliplatin-resistant human CRC.

Author Info: (1) Division of Molecular and Clinical Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan. (2) Division of Molecular and Clinical Genetics, Medical Institute of

Author Info: (1) Division of Molecular and Clinical Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan. (2) Division of Molecular and Clinical Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan. (3) Division of Molecular and Clinical Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan. Project Division of ALA Advanced Medical Research, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan. (4) Division of Molecular and Clinical Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan. Project Division of ALA Advanced Medical Research, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan. (5) Division of Molecular and Clinical Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan. Research Institute of Diseases of the Chest, Kyushu University, Fukuoka, Japan. (6) Division of Molecular and Clinical Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan. (7) Division of Molecular and Clinical Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan. (8) Project Division of ALA Advanced Medical Research, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan. (9) Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan. (10) Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan. (11) Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan. (12) Research Institute of Diseases of the Chest, Kyushu University, Fukuoka, Japan. (13) Division of Molecular and Clinical Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan k-tani@ims.u-tokyo.ac.jp. Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan. Project Division of ALA Advanced Medical Research, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan.

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Protective Epitope Discovery and the Design of MUC1 Based Vaccine for Effective Tumor Protections in Immunotolerant Mice

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Human mucin-1 (MUC1) is a highly attractive antigen for the development of anti-cancer vaccines. However, in human clinical trials of multiple MUC1 based vaccines, despite the generation of anti-MUC1 antibodies, the antibodies often failed to exhibit much binding to tumor presumably due to the challenges in inducing protective immune responses in the immunotolerant environment. To design effective MUC1 based vaccines functioning in immunotolerant hosts, vaccine constructs were first synthesized by covalently linking the powerful bacteriophage Qbeta carrier with MUC1 glycopeptides containing 20-22 amino acid residues covering one full length of the tandem repeat region of MUC1. However, IgG antibodies elicited by these first generation constructs in tolerant human MUC1 transgenic (Tg) mice did not bind tumor cells strongly. To overcome this, a peptide array has been synthesized. By profiling binding selectivities of antibodies, the long MUC1 glycopeptide was found to contain immunodominant but non-protective epitopes. Critical insights were obtained into the identity of the key protective epitope. Redesign of the vaccine focusing on the protective epitope led to a new Qbeta-MUC1 construct, which was capable of inducing higher levels of anti-MUC1 IgG antibodies in MUC1.Tg mice to react strongly with and kill a wide range of tumor cells compared to the construct containing the gold standard protein carrier, i.e., keyhole limpet hemocyanin. Vaccination with this new Qbeta-MUC1 conjugate led to significant protection of MUC1.Tg mice in both metastatic and solid tumor models. The antibodies exhibited remarkable selectivities towards human breast cancer tissues, suggesting its high translational potential.

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15)

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15)

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