Journal Articles

Antibody-based therapy

Therapies based on monoclonal antibodies, antibody derivatives, antibody-drug conjugates, bispecific antibodies, immunotoxins, etc. (except for immune checkpoint therapies)

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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Tumour endothelial marker 1/endosialin-mediated targeting of human sarcoma

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BACKGROUND: Tumour endothelial marker 1 (TEM1/endosialin/CD248) is a tumour-restricted cell-surface protein expressed by human sarcomas. We previously developed a high-affinity human single-chain variable fragment (scFv)-Fc fusion protein (78Fc) against TEM1 and demonstrated its specific binding to human and mouse TEM1. PATIENT AND METHODS: Clinical sarcoma specimens were collected between 2000 and 2015 at the Hospital of the University of Pennsylvania, as approved by the institutional review board and processed by standard formalin-fixed paraffin embedded techniques. We analysed TEM1 expression in 19 human sarcoma subtypes (n = 203 specimens) and eight human sarcoma-cell lines. Near-infrared (NIR) imaging of tumour-bearing mice was used to validate 78Fc binding to TEM1(+) sarcoma in vivo. Finally, we tested an immunotoxin conjugate of anti-TEM1 78Fc with saporin (78Fc-Sap) for its therapeutic efficacy against human sarcoma in vitro and in vivo. RESULTS: TEM1 expression was identified by immunohistochemistry in 96% of human sarcomas, of which 81% expressed TEM1 both on tumour cells and the tumour vasculature. NIR imaging revealed specific in vivo targeting of labelled 78Fc to TEM1(+) sarcoma xenografts. Importantly, 78Fc-Sap was effective in killing in vitro TEM1(+) sarcoma cells and eliminated human sarcoma xenografts without apparent toxicity in vivo. CONCLUSION: TEM1 is an important therapeutic target for human sarcoma, and the high-affinity TEM1-specific scFv fusion protein 78Fc is suitable for further clinical development for therapeutic applications in sarcoma.

Author Info: (1) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (2) Ovarian Cancer Research Center

Author Info: (1) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (2) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (3) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (4) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (5) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (6) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (7) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (8) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (9) Department of Pathology, People's Hospital, Peking University, PR China; Department of Pathology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (10) Department of Obstetrics and Gynecology, Tongji Hospital, Tongji University, PR China. (11) Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (12) Department of Pathology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (13) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA; Ludwig Institute for Cancer Research, University of Lausanne and Department of Oncology, University of Lausanne, 1007-CH, Switzerland. (14) Ludwig Institute for Cancer Research, University of Lausanne and Department of Oncology, University of Lausanne, 1007-CH, Switzerland. (15) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA; Ludwig Institute for Cancer Research, University of Lausanne and Department of Oncology, University of Lausanne, 1007-CH, Switzerland. Electronic address: george.coukos@chuv.ch. (16) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. Electronic address: lich@mail.med.upenn.edu.

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ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies

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Human CD19 antigen is a 95-kDa type I membrane glycoprotein in the immunoglobulin superfamily whose expression is limited to the various stages of B-cell development and differentiation and is maintained in the majority of B-cell malignancies, including leukemias and non-Hodgkin lymphomas of B-cell origin. Coupled with its differential and favourable expression profile, CD19 has rapid internalization kinetics and it is not shed into the circulation, making it an ideal target for the development of antibody-drug conjugates (ADCs) to treat B-cell malignancies. ADCT-402 (loncastuximab tesirine) is a novel CD19-targeted ADC delivering SG3199, a highly cytotoxic DNA minor groove interstrand cross-linking pyrrolobenzodiazepine (PBD) dimer warhead. It showed potent and highly targeted in vitro cytotoxicity in CD19-expressing human cell lines. ADCT-402 was specifically bound, internalized and trafficked to lysosomes in CD19-expressing cells and following release of warhead, resulted in formation of DNA cross-links which persisted for 36 h. Bystander killing of CD19-negative cells by ADCT-402 was also observed. In vivo, single doses of ADCT-402 resulted in highly potent, dose-dependent anti-tumor activity in several subcutaneous and disseminated human tumor models with marked superiority to comparator ADCs delivering tubulin inhibitors. Dose-dependent DNA cross-links and gamma-H2AX DNA damage response were measured in tumors by 24 h after single dose administration, while matched PBMCs showed no evidence of DNA damage. Pharmacokinetic analysis in rat and cynomolgus monkey showed excellent stability and tolerability of ADCT-402 in vivo. Together, these impressive data were used to support the clinical testing of this novel ADC in patients with CD19-expressing B-cell malignancies.

Author Info: (1) ADC Therapeutics (UK) Limited, London, United Kingdom; francesca.zammarchi@adctherapeutics.com. (2) Cancer Research UK Drug DNA Interactions Research Group, UCL Cancer Institute, London, United Kingdom. (3)

Author Info: (1) ADC Therapeutics (UK) Limited, London, United Kingdom; francesca.zammarchi@adctherapeutics.com. (2) Cancer Research UK Drug DNA Interactions Research Group, UCL Cancer Institute, London, United Kingdom. (3) Spirogen/Medimmune Ltd, London, United Kingdom. (4) Spirogen/Medimmune Ltd, London, United Kingdom. (5) Cancer Research UK Drug DNA Interactions Research Group, UCL Cancer Institute, London, United Kingdom. (6) Department of Pathology, UCL Cancer Institute, London, United Kingdom. (7) Department of Pathology, UCL Cancer Institute, London, United Kingdom. (8) ADC Therapeutics (UK) Limited, London, United Kingdom. (9) ADC Therapeutics (UK) Limited, London, United Kingdom. (10) ADC Therapeutics (UK) Limited, London, United Kingdom. (11) Spirogen/Medimmune Ltd, London, United Kingdom. (12) Spirogen/Medimmune Ltd, London, United Kingdom. (13) Spirogen/Medimmune Ltd, London, United Kingdom. (14) Spirogen/Medimmune Ltd, London, United Kingdom. (15) Cancer Research UK Drug DNA Interactions Research Group, UCL Cancer Institute, London, United Kingdom. (16) ADC Therapeutics (UK) Limited, London, United Kingdom.

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Antibody based EpCAM targeted Therapy of Cancer, Review and update

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Todays, after four decades of the discovery of monoclonal antibodies by Kohler and Milstein in 1975, a dozen of antibodies are used in cancer targeted therapy with different strategies. The success of these antibodies depends on the specificity of antigens expressed on the cancer cells. Epithelial cell adhesion molecule (EpCAM), a homophilic cell-cell adhesion glycoprotein is a well- known tumor antigen, which expresses on epithelial tumors and circulating tumor cells as well as cancer stem cells. The EpCAM signaling pathway is associated with proliferation, differentiation and adhesion of epithelial cancer cells. Here we review EpCAM structure, expression profile and its signaling pathway in cancer cells. In addition, we focused on structure, mechanism of action and success of anti EpCAM antibodies which have been used in different clinical trials. Based on literatures, Edrecolomab show limited efficacy in the phase III studies. The wholly monoclonal antibody Adecatumumab is dose- and target-dependent in metastatic breast cancer patients expressing EpCAM. The chimeric antibody Catumaxomab is approved for the treatment of malignant ascites; however, this Mab showed considerable results in intrapleural administration in cancer patients. Anti EpCAM toxin conjugated antibodies Oportuzumab Monatox (scFv antibody and Pseudomonas exotoxin A (ETA)) and Citatuzumab Bogatox (Fab fragment with bouganin toxin) and also, immono-conjugate antibody Tucotuzumab (wholly monoclonal antibody with IL2), shown acceptable results in different clinical trials. Almost, all of the antibodies were well- tolerated; however, still more clinical trials are needed for approval of the antibodies for treatment of specific tumors.

Author Info: (1) Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran. Iran. (2) Biotechnology Research Center, Tabriz University of

Author Info: (1) Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran. Iran. (2) Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz. Iran. (3) Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz. Iran. (4) Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz. Iran. (5) Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Science. Tabriz. Iran. (6) Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran. Iran.

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Phase 1 trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-beta, in advanced solid tumors

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PURPOSE: M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a monoclonal antibody against programmed death ligand 1 (PD-L1) fused to a transforming growth factor-beta (TGF-beta) "trap." Experimental DesignIn the 3+3 dose-escalation component of this phase 1 study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once-every-2-weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; additionally, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/pharmacodynamics (PK/PD), followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include PK, immunogenicity, and best overall response. RESULTS: Nineteen heavily pretreated patients with ECOG 0-1 have received M7824. Grade >/=3 treatment-related adverse events occurred in 4 patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGF-beta1, -beta2, and -beta3 throughout the dosing period at >1 mg/kg. There were signs of efficacy across all dose levels, including 1 ongoing confirmed complete response (cervical cancer), 2 durable confirmed partial responses (PRs; pancreatic cancer; anal cancer), 1 near-PR (cervical cancer), and 2 cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid). CONCLUSIONS: M7824 has a manageable safety profile in patients with heavily pretreated advanced solid tumors. Early signs of efficacy are encouraging and multiple expansion cohorts are ongoing in a range of tumors.

Author Info: (1) Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health. (2) Laboratory of Tumor Immunology and Biology, National Cancer Institute, National

Author Info: (1) Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health. (2) Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health. (3) Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health. (4) Genitourinary Malignancies Branch, National Cancer Institute. (5) Genetics Branch, National Cancer Institute. (6) Genetic Branch, National Cancer Institute. (7) Office of Research Nursing, National Cancer Institute, National Institutes of Health. (8) Laboratory of Tumor Immunology and Biology, National Cancer Institute. (9) Laboratory of Tumor Immunology and Biology, National Cancer Institute. (10) Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health. (11) Genitourinary Malignancies Branch,, Center for Cancer Research, National Cancer Institute. (12) EMD Serono. (13) Global Exploratory Development, EMD Serono. (14) Merck KGaA. (15) Genitourinary Malignancies Branch, ational Cancer Institute, National Institutes of Health gulleyj@mail.nih.gov.

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ATTACK, a novel bispecific T cell-recruiting antibody with trivalent EGFR binding and monovalent CD3 binding for cancer immunotherapy

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The redirection of T cell activity using bispecific antibodies is one of the most promising cancer immunotherapy approaches currently in development, but it is limited by cytokine storm-related toxicities, as well as the pharmacokinetics and tumor-penetrating capabilities of current bispecific antibody formats. Here, we have engineered the ATTACK (Asymmetric Tandem Trimerbody for T cell Activation and Cancer Killing), a novel T cell-recruiting bispecific antibody which combines three EGFR-binding single-domain antibodies (VHH; clone EgA1) with a single CD3-binding single-chain variable fragment (scFv; clone OKT3) in an intermediate molecular weight package. The two specificities are oriented in opposite directions in order to simultaneously engage cancer cells and T cell effectors, and thereby promote immunological synapse formation. EgA1 ATTACK was expressed as a homogenous, non-aggregating, soluble protein by mammalian cells and demonstrated an enhanced binding to EGFR, but not CD3, when compared to the previously characterized tandem bispecific antibody which has one EgA1 VHH and one OKT3 scFv per molecule. EgA1 ATTACK induced synapse formation and early signaling pathways downstream of TCR engagement at lower concentrations than the tandem VHH-scFv bispecific antibody. Furthermore, it demonstrated extremely potent, dose-dependent cytotoxicity when retargeting human T cells towards EGFR-expressing cells, with an efficacy over 15-fold higher than that of the tandem VHH-scFv bispecific antibody. These results suggest that the ATTACK is an ideal format for the development of the next-generation of T cell-redirecting bispecific antibodies.

Author Info: (1) Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, Aarhus, Denmark. (2) Department of Antibody Engineering, Leadartis SL, Madrid, Spain. (3) Immunotherapy and

Author Info: (1) Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, Aarhus, Denmark. (2) Department of Antibody Engineering, Leadartis SL, Madrid, Spain. (3) Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, Aarhus, Denmark. (4) Department of Antibody Engineering, Leadartis SL, Madrid, Spain. (5) Department of Microbiology I (Immunology), School of Medicine, Universidad Complutense de Madrid, Madrid, Spain; Instituto de Investigacion Sanitaria 12 de Octubre (imas12), Madrid, Spain. (6) Structural Biology Unit, CIC bioGUNE, Parque Tecnologico de Bizkaia, Bizkaia, Derio, Spain. (7) Laboratory of Protein Design and Immunoengineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland. (8) Molecular Immunology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain. (9) Division of Cell Biology, Department of Biology, Science Faculty, Utrecht University, Utrecht, The Netherlands. (10) Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, Aarhus, Denmark. (11) Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, Aarhus, Denmark. (12) Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, Aarhus, Denmark. (13) Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, Aarhus, Denmark. (14) Molecular Immunology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain. (15) Structural Biology Unit, CIC bioGUNE, Parque Tecnologico de Bizkaia, Bizkaia, Derio, Spain. IKERBASQUE, Basque Foundation for Science, Bizkaia, Bilbao, Spain. (16) Department of Microbiology I (Immunology), School of Medicine, Universidad Complutense de Madrid, Madrid, Spain; Instituto de Investigacion Sanitaria 12 de Octubre (imas12), Madrid, Spain. (17) Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, Aarhus, Denmark.

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A bispecific nanobody approach to leverage the potent and widely applicable tumor cytolytic capacity of Vgamma9Vdelta2-T cells

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Though Vgamma9Vdelta2-T cells constitute only a small fraction of the total T cell population in human peripheral blood, they play a vital role in tumor defense and are therefore of major interest to explore for cancer immunotherapy. Vgamma9Vdelta2-T cell-based cancer immunotherapeutic approaches developed so far have been generally well tolerated and were able to induce significant clinical responses. However, overall results were inconsistent, possibly due to the fact that these strategies induced systemic activation of Vgamma9Vdelta2-T cells without preferential accumulation and targeted activation in the tumor. Here we show that a novel bispecific nanobody-based construct targeting both Vgamma9Vdelta2-T cells and EGFR induced potent Vgamma9Vdelta2-T cell activation and subsequent tumor cell lysis both in vitro and in an in vivo mouse xenograft model. Tumor cell lysis was independent of KRAS and BRAF tumor mutation status and common Vgamma9Vdelta2-T cell receptor sequence variations. In combination with the conserved monomorphic nature of the Vgamma9Vdelta2-TCR and the facile replacement of the tumor-specific nanobody, this immunotherapeutic approach can be applied to a large group of cancer patients.

Author Info: (1) Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (2) Department of Medical Oncology, VU University Medical

Author Info: (1) Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (2) Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (3) Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (4) Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (5) Innate Immunity Unit, Institut Pasteur, Paris, France. Institut National de la Sante et de la Recherche Medicale (INSERM) U1223, Paris, France. Universite Paris-Sud, Universite Paris-Saclay, Gif-sur-Yvette, France. (6) Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (7) Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (8) Department of Hematology and Laboratory of Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. (9) Department of Hematology and Laboratory of Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. (10) Department of Radiology and Nuclear Medicine, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (11) Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (12) Department of Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands. (13) Innate Immunity Unit, Institut Pasteur, Paris, France. Institut National de la Sante et de la Recherche Medicale (INSERM) U1223, Paris, France. (14) Department of Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands. (15) Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (16) Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. (17) Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.

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CD89-mediated recruitment of macrophages via a bispecific antibody enhances anti-tumor efficacy

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Since tumors are often infiltrated by macrophages, it would be advantageous to turn these types of cells into cytotoxic effector cells. Here, we have designed a novel bispecific antibody (BsAb) that targets both tumor antigen (CD20) and the FcalphaRI receptor (CD89). This antibody could be used to lyse tumors by connecting tumor cells to CD89-expressing immune effector cells such as macrophages and neutrophils. Previously there were very limited attempts to exploit FcalphaRI-expressing cells as effector cells for tumor cell-killing, largely due to the lack of an appropriate in vivo model, since mice do not express a human CD89 homolog. In this study, we used a transgenic mouse strain with specific expression of CD89 on macrophages and monocytes. In this transgenic mouse model, the CD89 bispecific antibody showed significant anti-tumor activities, demonstrating that bispecific antibodies can redirect macrophages, including M2 macrophages, to mediate additional effector function in the tumor microenvironment. This approach realized the full potential of the innate immune system and could be applied to other tumor-associated antigens especially the solid tumors, thus has potential to translate into clinical benefits in human cancers.

Author Info: (1) School of Life Sciences and Technology, Tongji University, Shanghai, China. (2) School of Life Sciences and Technology, Tongji University, Shanghai, China. College of Medicine

Author Info: (1) School of Life Sciences and Technology, Tongji University, Shanghai, China. (2) School of Life Sciences and Technology, Tongji University, Shanghai, China. College of Medicine, Henan University of Science and Technology, Luoyang, Henan, China. (3) School of Life Sciences and Technology, Tongji University, Shanghai, China. (4) Biomedical Research Center, Tongji University Suzhou Institute, Suzhou, Jiangsu, China. (5) School of Life Sciences and Technology, Tongji University, Shanghai, China. (6) School of Life Sciences and Technology, Tongji University, Shanghai, China. (7) School of Life Sciences and Technology, Tongji University, Shanghai, China. (8) School of Life Sciences and Technology, Tongji University, Shanghai, China. (9) School of Life Sciences and Technology, Tongji University, Shanghai, China. Shanghai Tongji Hospital, Tongji University, Shanghai, China. Biomedical Research Center, Tongji University Suzhou Institute, Suzhou, Jiangsu, China. Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

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Bevacizumab-mediated tumor vasculature remodelling improves tumor infiltration and antitumor efficacy of GD2-CAR T cells in a human neuroblastoma preclinical model

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GD2-redirected chimeric antigen receptor (CAR) T lymphocytes represent a promising therapeutic option for immunotherapy of neuroblastoma (NB). However, despite the encouraging therapeutic effects observed in some hematological malignancies, clinical results of CAR T cell immunotherapy in solid tumors are still modest. Tumor driven neo-angiogenesis supports an immunosuppressive microenvironment that influences treatment responses and is amenable to targeting with antiangiogenic drugs. The latter agents promote lymphocyte tumor infiltration by transiently reprogramming tumor vasculature, and may represent a valid combinatorial approach with CAR T cell immunotherapy. In light of these considerations, we investigated the anti-NB activity of GD2-CAR T cells combined with bevacizumab (BEV) in an orthotopic xenograft model of human NB. Two weeks after tumor implantation, mice received BEV or GD2-CAR T cells or both by single intravenous administration. GD2-CAR T cells exerted a significant anti-NB activity only in combination with BEV, even at the lowest concentration tested, which per se did not inhibit tumor growth. When combined with BEV, GD2-CAR T cells massively infiltrated tumor mass where they produced interferon-gamma (IFN-gamma), which, in turn, induced expression of CXCL10 by NB cells. IFN-gamma, and possibly other cytokines, upregulated NB cell expression of PD-L1, while tumor infiltrating GD2-CAR T cells expressed PD-1. Thus, the PD-1/PD-L1 axis can limit the anti-tumor efficacy of the GD2-CAR T cell/BEV association. This study provides a strong rationale for testing the combination of GD2-CAR T cells with BEV in a clinical trial enrolling NB patients. PD-L1 silencing or blocking strategies may further enhance the efficacy of such combination.

Author Info: (1) Laboratory of Oncology, Dep. of Translational Research, IRCCS Istituto G. Gaslini, Genova, Italy. (2) Anatomic Pathology and Molecular Medicine, Dep. of Medicine and Sciences

Author Info: (1) Laboratory of Oncology, Dep. of Translational Research, IRCCS Istituto G. Gaslini, Genova, Italy. (2) Anatomic Pathology and Molecular Medicine, Dep. of Medicine and Sciences of Aging, "G. d'Annunzio" University, Chieti, Italy. Ce. S. I.-MeT, Aging Research Center, Pathological Anatomy and Immuno-Oncology Unit, "G. d'Annunzio" University, Chieti, Italy. (3) Laboratory of Cell and Gene Therapy of Pediatric Tumors, Dep. of Hematology/Oncology, IRCCS Ospedale Pediatrico Bambino Gesu, Roma, Italy. (4) S.S.D. Animal Facility, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, Genova, Italy. (5) S.S.D. Animal Facility, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, Genova, Italy. (6) Laboratory of Cell and Gene Therapy of Pediatric Tumors, Dep. of Hematology/Oncology, IRCCS Ospedale Pediatrico Bambino Gesu, Roma, Italy. (7) Laboratory of Cell and Gene Therapy of Pediatric Tumors, Dep. of Hematology/Oncology, IRCCS Ospedale Pediatrico Bambino Gesu, Roma, Italy. Dipartimento di Medicina Clinica e Chirurgia, Universita degli Studi di Napoli Federico II, Napoli, Italy. (8) Laboratory of Oncology, Dep. of Translational Research, IRCCS Istituto G. Gaslini, Genova, Italy. (9) Laboratory of Oncology, Dep. of Translational Research, IRCCS Istituto G. Gaslini, Genova, Italy. (10) Laboratory of Oncology, Dep. of Translational Research, IRCCS Istituto G. Gaslini, Genova, Italy. (11) Laboratory of Cell and Gene Therapy of Pediatric Tumors, Dep. of Hematology/Oncology, IRCCS Ospedale Pediatrico Bambino Gesu, Roma, Italy. Department of Pediatrics, Universita di Pavia, Pavia, Italy. (12) Immunology Area, IRCCS Ospedale Pediatrico Bambino Gesu, Roma, Italy. (13) Laboratory of Oncology, Dep. of Translational Research, IRCCS Istituto G. Gaslini, Genova, Italy.

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Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma

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Daratumumab, a human CD38 imunoglobulin G 1kappa monoclonal antibody, has demonstrated clinical activity and a manageable safety profile in monotherapy and combination therapy clinical trials in relapsed and/or refractory multiple myeloma. CD38 is expressed at high levels on myeloma cells and, to a lesser extent, on immune effector cells, including natural killer (NK) cells, which are important for daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Here, the pharmacodynamic effects of daratumumab monotherapy on NK cells, and the effect of NK cell dynamics on daratumumab efficacy and safety, were assessed. Daratumumab, like other CD38 antibodies, reduced NK-cell counts in peripheral blood mononuclear cells (PBMCs) of healthy donors in vitro. Data on NK-cell counts, clinical efficacy, and adverse events were pooled from two single-agent daratumumab studies, GEN501 and SIRIUS. In daratumumab-treated myeloma patients, total and activated NK-cell counts reduced rapidly in peripheral blood after the first dose, remained low over the course of treatment, and recovered after treatment ended. There was a clear maximum effect relationship between daratumumab dose and maximum reduction in NK cells. Similar reductions were observed in bone marrow. PBMCs from daratumumab-treated patients induced lysis by ADCC of CD38(+) tumor cells in vitro, suggesting that the remaining NK cells retained cytotoxic functionality. There was no relationship between NK-cell count reduction and the efficacy or safety profile of daratumumab. Furthermore, although NK cell numbers are reduced after daratumumab treatment, they are not completely depleted and may still contribute to ADCC, clinical efficacy, and infection control.

Author Info: (1) Janssen Research & Development, Beerse, Belgium. (2) Janssen Research & Development, LLC, Raritan, NJ. (3) Janssen Research & Development, LLC, Spring House, PA. (4)

Author Info: (1) Janssen Research & Development, Beerse, Belgium. (2) Janssen Research & Development, LLC, Raritan, NJ. (3) Janssen Research & Development, LLC, Spring House, PA. (4) Janssen Research & Development, LLC, Spring House, PA. (5) Janssen Research & Development, LLC, Spring House, PA. (6) Janssen Research & Development, LLC, Raritan, NJ. (7) Janssen Research & Development, LLC, Spring House, PA. (8) Janssen Research & Development, LLC, Raritan, NJ. (9) Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA. (10) Vejle Hospital and University of Southern Denmark, Vejle, Denmark; and. (11) Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands. (12) Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands. (13) Janssen Research & Development, LLC, Spring House, PA. (14) Janssen Research & Development, LLC, Spring House, PA.

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