Journal Articles

Ibrutinib treatment inhibits breast cancer progression and metastasis by inducing conversion of myeloid-derived suppressor cells to dendritic cell

BACKGROUND: Ibrutinib is a Bruton's tyrosine kinase (BTK) and interleukin-2-inducible kinase (ITK) inhibitor used for treating chronic lymphocytic leukaemia (CLL) and other cancers. Although ibrutinib is known to inhibit the growth of breast cancer cell growth in vitro, its impact on the treatment and metastasis of breast cancer is unclear. METHODS: Using an orthotopic mouse breast cancer model, we show that ibrutinib inhibits the progression and metastasis of breast cancer. RESULTS: Ibrutinib inhibited proliferation of cancer cells in vitro, and Ibrutinib-treated mice displayed significantly lower tumour burdens and metastasis compared to controls. Furthermore, the spleens and tumours from Ibrutinib-treated mice contained more mature DCs and lower numbers of myeloid-derived suppressor cells (MDSCs), which promote disease progression and are linked to poor prognosis. We also confirmed that ex vivo treatment of MDSCs with ibrutinib switched their phenotype to mature DCs and significantly enhanced MHCII expression. Further, ibrutinib treatment promoted T cell proliferation and effector functions leading to the induction of antitumour TH1 and CTL immune responses. CONCLUSIONS: Ibrutinib inhibits tumour development and metastasis in breast cancer by promoting the development of mature DCs from MDSCs and hence could be a novel therapeutic agent for the treatment of breast cancer.

Author Info: (1) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (2) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA.

Author Info: (1) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (2) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (3) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. Department of Microbiology, The Ohio State University, Columbus, OH, USA. (4) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (5) Department of Infection and Immunity, The Ohio State University, Columbus, OH, USA. (6) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (7) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (8) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (9) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (10) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (11) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (12) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (13) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (14) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (15) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. abhay.satoskar@osumc.edu. Department of Microbiology, The Ohio State University, Columbus, OH, USA. abhay.satoskar@osumc.edu.

Prostaglandin E2 in a TLR3- and 7/8-agonist-based DC maturation cocktail generates mature, cytokine-producing, migratory DCs but impairs antigen cross-presentation to CD8(+) T cells

Mature dendritic cells (DCs) represent cellular adjuvants for optimal antigen presentation in cancer vaccines. Recently, a combination of prostaglandin E2 (PGE2) with Toll-like receptor agonists (TLR-P) was proposed as a new standard to generate superior cytokine-producing DCs with high migratory capacity. Here, we compare TLR-P DCs with conventional DCs matured only with the proinflammatory cytokines TNFalpha and IL-1ss (CDCs), focussing on the interaction of resulting DCs with CD8(+) T-cells. TLR-P matured DCs showed elevated expression of activation markers such as CD80 and CD83 compared to CDCs, together with a significantly higher migration capacity. Secretion of IL-6, IL-8, IL-10, and IL-12 was highest after 16 h in TLR-P DCs, and only TLR-P DCs secreted active IL-12p70. TLR-P DCs as well as CDCs successfully primed multifunctional CD8(+) T-cells from naive precursors specific for the peptide antigens Melan-A, NLGN4X, and PTP with comparable priming efficacy and T-cell receptor avidity. CD8(+) T-cells primed by TLR-P DCs showed significantly elevated expression of the integrin VLA-4 and a trend for higher T-cell numbers after expansion. In contrast, TLR-P DCs displayed a substantially reduced capability to cross-present CMVpp65 protein antigen to pp65-specific T cells, an effect that was dose-dependent on PGE2 during DC maturation and reproducible with several responder T-cell lines. In conclusion, TLR-P matured DCs might be optimal presenters of antigens not requiring processing such as short peptides. However, PGE2 seems less favorable for maturation of DCs intended to process and cross-present more complex vaccine antigens such as lysates, proteins or long peptides.

Author Info: (1) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (2) Laboratory for Stem Cell Processing and Cellular

Author Info: (1) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (2) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (3) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (4) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (5) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (6) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (7) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (8) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (9) CU Systems Medicine, University of Wurzburg, Wurzburg, Germany. Max Delbruck Center for Molecular Medicine (BIMSB/BIH), Berlin, Germany. (10) Department of Immunology, Interfaculty Institute for Cell Biology, University of Tubingen, Tubingen, Germany. (11) Department of Internal Medicine II, University Medical Center, Wurzburg, Germany. (12) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (13) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (14) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. eyrich_m@ukw.de. University Children's Hospital Wurzburg, Josef-Schneider-Strasse 3, Building D30, 97080, Wurzburg, Germany. eyrich_m@ukw.de.

Prediction and identification of novel HLA-A*0201-restricted cytotoxic T lymphocyte epitopes from endocan

Background: Prediction and identification of cytotoxic T lymphocyte (CTL) epitopes from tumor associated antigens is a crucial step for the development of tumor immunotherapy strategy. Endocan has been identified as antigen overexpressed in various tumors. Methods: In this experiment, we predicted and identified HLA-A2-restricted CTL epitopes from endocan by using the following procedures. Firstly, we predicted the epitopes from the amino acid sequence of endocan by computer-based methods; Secondly, we determined the affinity of the predicted peptide with HLA-A2.1 molecule by peptide-binding assay; Thirdly, we elicited the primary T cell response against the predicted peptides in vitro; Lastly, we tested the specific CTLs toward endocan and HLA-A2.1 positive target cells. Results: These data demonstrated that peptides of endocan containing residues 4-12 and 9-17 could elicit specific CTLs producing interferon-gamma and cytotoxicity. Conclusions: Therefore, our findings suggested that the predicted peptides were novel HLA-A2.1-restricted CTL epitopes, and might provide promising target for tumor immunotherapy.

Author Info: (1) 1Department of orthopedics, Yongchuan Hospital, Chongqing Medical University, Chongqing, 402160 China.grid.203458.80000 0000 8653 0555 (2) 2Department of Neurology and Chongqin

Author Info: (1) 1Department of orthopedics, Yongchuan Hospital, Chongqing Medical University, Chongqing, 402160 China.grid.203458.80000 0000 8653 0555 (2) 2Department of Neurology and Chongqing key laboratory of cerebravascular disease, Yongchuan Hospital, Chongqing Medical University, Chongqing, 402160 China.grid.203458.80000 0000 8653 0555 (3) 2Department of Neurology and Chongqing key laboratory of cerebravascular disease, Yongchuan Hospital, Chongqing Medical University, Chongqing, 402160 China.grid.203458.80000 0000 8653 0555 (4) 2Department of Neurology and Chongqing key laboratory of cerebravascular disease, Yongchuan Hospital, Chongqing Medical University, Chongqing, 402160 China.grid.203458.80000 0000 8653 0555 (5) 2Department of Neurology and Chongqing key laboratory of cerebravascular disease, Yongchuan Hospital, Chongqing Medical University, Chongqing, 402160 China.grid.203458.80000 0000 8653 0555 (6) 2Department of Neurology and Chongqing key laboratory of cerebravascular disease, Yongchuan Hospital, Chongqing Medical University, Chongqing, 402160 China.grid.203458.80000 0000 8653 0555 (7) 2Department of Neurology and Chongqing key laboratory of cerebravascular disease, Yongchuan Hospital, Chongqing Medical University, Chongqing, 402160 China.grid.203458.80000 0000 8653 0555

CCL5-armed oncolytic virus augments CCR5-engineered NK cell infiltration and antitumor efficiency

BACKGROUND: Natural killer (NK) cells have potent antitumor activities. Nevertheless, adoptive transfer therapy of NK cells has gained very limited success in patients with solid tumors as most infused NK cells remain circulating in the peripheral blood instead of entering tumor sites. Chemokines and their receptors play important roles in NK cell distribution. Enhancing chemokine receptors on immune cells to match and be driven to tumor-specific chemokines may improve the therapeutic efficacy of NK cells. METHODS: The CCR5-CCL5 axis is critical in NK cell homing to tumor sites. Thus, we analyzed CCR5 expression on NK cells from patients with cancer and healthy donors. We then upregulated CCR5 and CCL5 with lentiviruses and oncolytic viruses in NK and tumor cells, respectively. Animal experiments were also carried out to test the efficacy of the combination of oncolytic virus with NK cells. RESULTS: In NK cells from patients with various solid tumors or healthy subjects, CCR5 was expressed at low levels before and after expansion in vitro. CCR5-engineered NK cells showed enhanced tumor infiltration and antitumor effects, but no complete regressions were noted in the in vivo tumor models. To further improve therapeutic efficacy, we constructed CCL5-expressing oncolytic vaccinia virus. In vitro data demonstrated that vaccinia virus can produce CCL5 in tumor cells while infectivity remained unaffected. Supernatants from tumor cells infected by CCL5-modified vaccinia virus enhanced the directional movement of CCR5-overexpressed NK cells but not green fluorescent protein (GFP)-expressing cells. More importantly, NK cells were resistant to the vaccinia virus and their functions were not affected after being in contact. In vivo assays demonstrated that CCL5-expressing vaccinia virus induced a greater accumulation of NK cells within tumor lesions compared with that of the prototype virus. CONCLUSION: Enhancement of matched chemokines and chemokine receptors is a promising method of increasing NK cell homing and therapeutic effects. Oncolytic vaccinia viruses that express specific chemokines can synergistically augment the efficacies of NK cell-based therapy.

Author Info: (1) Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China yizhang@zzu.edu.cn steve.thorne@westernoncolytics.com lifeng01@msn.com.

Author Info: (1) Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China yizhang@zzu.edu.cn steve.thorne@westernoncolytics.com lifeng01@msn.com. Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China. Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA. (2) Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA. Medical Research Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China. (3) Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA. (4) Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA. (5) Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA. (6) Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA yizhang@zzu.edu.cn steve.thorne@westernoncolytics.com lifeng01@msn.com. (7) Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China yizhang@zzu.edu.cn steve.thorne@westernoncolytics.com lifeng01@msn.com. Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.

The Cancer Microbiome: Distinguishing Direct and Indirect Effects Requires a Systemic View

The collection of microbes that live in and on the human body - the human microbiome - can impact on cancer initiation, progression, and response to therapy, including cancer immunotherapy. The mechanisms by which microbiomes impact on cancers can yield new diagnostics and treatments, but much remains unknown. The interactions between microbes, diet, host factors, drugs, and cell-cell interactions within the cancer itself likely involve intricate feedbacks, and no single component can explain all the behavior of the system. Understanding the role of host-associated microbial communities in cancer systems will require a multidisciplinary approach combining microbial ecology, immunology, cancer cell biology, and computational biology - a systems biology approach.

Author Info: (1) Program for Computational and Systems Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Electronic address: xavierj@mskcc.org. (2) Department of Internal Medi

Author Info: (1) Program for Computational and Systems Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Electronic address: xavierj@mskcc.org. (2) Department of Internal Medicine, Division of Infectious Diseases, The University of Michigan Medical School, Ann Arbor, MI, USA. (3) Department of Mathematics, Clarkson University, Potsdam, NY, USA. (4) GE Research, Niskayuna, NY, USA. (5) Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA. (6) Section of Hematology/Oncology, Department of Medicine, Comprehensive Cancer Center, University of Chicago, Chicago, Illinois, IL, USA. (7) Intelligent Systems Engineering, Indiana University, Bloomington, IN, USA. (8) Program in Systems Biology, University of Massachusetts Medical School, Worcester, MA, USA. (9) Institute for Systems Biology, Seattle, WA, USA. (10) Hunter College, Department of Computer Science, New York, NY, USA. (11) Center for Applied Microbiome Science, Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, USA. (12) Computational Biology Institute, Milken Institute School of Public Health, George Washington University, Washington, DC, USA. (13) Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. (14) Department of Microbiology and Medical Zoology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico. (15) Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA. (16) Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA. (17) Seattle Children's Research Institute, Ben Towne Center for Childhood Cancer Research, Seattle, WA, USA. (18) Department of Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA. (19) University of Michigan, Ann Arbor, MI, USA. (20) Department of Surgery, Department of Obstetrics and Gynecology, and Microbiome Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA. (21) Department of Systems Biology, Columbia University, New York, NY, USA. (22) Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA. (23) School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, USA. (24) Division of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA. (25) Departments of Medicine, Anatomy, and Cell Biology, and of Infectious Diseases and Immunology, University of Florida, Gainesville, FL, USA. (26) Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA. (27) University of Texas Southwestern Medical Center, Dallas, TX, USA. (28) Toyota Technological Institute at Chicago, Chicago, IL, USA. (29) Albert Einstein College of Medicine, Bronx, NY, USA. (30) The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Hyperprogression and Immunotherapy: Fact, Fiction, or Alternative Fact

Immunotherapy (IO) has altered the therapeutic landscape for multiple cancers. There are emerging data from retrospective studies on a subset of patients who do not benefit from IO, instead experiencing rapid progression with dramatic acceleration of disease trajectory, termed 'hyperprogressive disease' (HPD). The incidence of HPD ranges from 4% to 29% from the studies reported. Biological basis and mechanisms of HPD are currently being elucidated, with one theory involving the Fc region of antibodies. Another group has shown EGFR and MDM2/MDM4 amplifications in patients with HPD. This phenomenon has polarized oncologists who debate that this could still reflect the natural history of the disease. Thus, prospective studies are urgently needed to confirm the underlying biology, predict patients who are susceptible to HPD, and determine the modality of therapy post progression.

Author Info: (1) University of South Florida, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (2) The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Val

Author Info: (1) University of South Florida, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (2) The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Vall Hebron Institute, Madrid, Spain. (4) Vall Hebron Institute, Madrid, Spain. (5) The University of Texas at Austin, Austin, TX, USA. (6) The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: vsubbiah@mdanderson.org.

Combination of chemotherapy and PD-1 blockade induces T cell responses to tumor non-mutated neoantigens

Here, we developed an unbiased, functional target-discovery platform to identify immunogenic proteins from primary non-small cell lung cancer (NSCLC) cells that had been induced to apoptosis by cisplatin (CDDP) treatment in vitro, as compared with their live counterparts. Among the multitude of proteins identified, some of them were represented as fragmented proteins in apoptotic tumor cells, and acted as non-mutated neoantigens (NM-neoAgs). Indeed, only the fragmented proteins elicited effective multi-specific CD4(+) and CD8(+) T cell responses, upon a chemotherapy protocol including CDDP. Importantly, these responses further increased upon anti-PD-1 therapy, and correlated with patients' survival and decreased PD-1 expression. Cross-presentation assays showed that NM-neoAgs were unveiled in apoptotic tumor cells as the result of caspase-dependent proteolytic activity of cellular proteins. Our study demonstrates that apoptotic tumor cells generate a repertoire of immunogenic NM-neoAgs that could be potentially used for developing effective T cell-based immunotherapy across multiple cancer patients.

Author Info: (1) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (2) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Univ

Author Info: (1) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (2) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (3) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (4) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (5) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (6) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (7) Dipartimento di Medicina Molecolare, Sapienza Universita di Roma, 00161, Rome, Italy. (8) Dipartimento di Scienze Radiologiche, Oncologiche e Anatomo Patologiche, Oncologia Medica, Universita di Roma, 00161, Rome, Italy. (9) Dipartimento di Scienze Radiologiche, Oncologiche e Anatomo Patologiche, Oncologia Medica, Universita di Roma, 00161, Rome, Italy. (10) Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy. (11) Dipartimento di Scienze Radiologiche, Oncologiche e Anatomo Patologiche, Oncologia Medica, Universita di Roma, 00161, Rome, Italy. (12) Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy. IRCCS Neuromed, Pozzilli, Isernia, Italy. (13) Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza Universita di Roma - Polo Pontino, 04100, Latina, Italy. (14) Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza Universita di Roma - Polo Pontino, 04100, Latina, Italy. (15) UOC Oncologia Universitaria, ASL Latina (distretto Aprilia), Sapienza Universita di Roma, Via Giustiniano snc, 04011, Aprilia, Latina, Italy. (16) Dipartimento di Medicina Molecolare, Sapienza Universita di Roma, 00161, Rome, Italy. (17) Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161, Rome, Italy. (18) Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy. (19) Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy. (20) Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy. (21) Medical Oncology 1, IRCCS-Regina Elena National Cancer Institute, Rome, Italy. (22) Unit of Pathology, IRCCS-Regina Elena National Cancer Institute, Rome, Italy. (23) Thoracic Surgery Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy. (24) Dipartimento di Scienze Radiologiche, Oncologiche e Anatomo Patologiche, Oncologia Medica, Universita di Roma, 00161, Rome, Italy. (25) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. vincenzo.barnaba@uniroma1.it. Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161, Rome, Italy. vincenzo.barnaba@uniroma1.it. Istituto Pasteur - Fondazione Cenci Bolognetti, 00185, Rome, Italy. vincenzo.barnaba@uniroma1.it.

DNA-Based Delivery of Checkpoint Inhibitors in Muscle and Tumor Enables Long-Term Responses with Distinct Exposure

Checkpoint-inhibiting antibodies elicit impressive clinical responses, but still face several issues. The current study evaluated whether DNA-based delivery can broaden the application of checkpoint inhibitors, specifically by pursuing cost-efficient in vivo production, facilitating combination therapies, and exploring administration routes that lower immune-related toxicity risks. We therefore optimized plasmid-encoded anti-CTLA-4 and anti-PD-1 antibodies, and studied their pharmacokinetics and pharmacodynamics when delivered alone and in combination via intramuscular or intratumoral electroporation in mice. Intramuscular electrotransfer of these DNA-based antibodies induced complete regressions in a subcutaneous MC38 tumor model, with plasma concentrations up to 4 and 14 mug/mL for anti-CTLA-4 and anti-PD-1 antibodies, respectively, and antibody detection for at least 6 months. Intratumoral antibody gene electrotransfer gave similar anti-tumor responses as the intramuscular approach. Antibody plasma levels, however, were up to 70-fold lower and substantially more transient, potentially improving biosafety of the expressed checkpoint inhibitors. Intratumoral delivery also generated a systemic anti-tumor response, illustrated by moderate abscopal effects and prolonged protection of cured mice against a tumor rechallenge. In conclusion, intramuscular and intratumoral DNA-based delivery of checkpoint inhibitors both enabled long-term anti-tumor responses despite distinct systemic antibody exposure, highlighting the potential of the tumor as delivery site for DNA-based therapeutics.

Author Info: (1) Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven - University of Leuven, Leuven, Belgium. (2) Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven - U

Author Info: (1) Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven - University of Leuven, Leuven, Belgium. (2) Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven - University of Leuven, Leuven, Belgium; PharmAbs - The KU Leuven Antibody Center, KU Leuven - University of Leuven, Leuven, Belgium. (3) PharmAbs - The KU Leuven Antibody Center, KU Leuven - University of Leuven, Leuven, Belgium. (4) Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven - University of Leuven, Leuven, Belgium; PharmAbs - The KU Leuven Antibody Center, KU Leuven - University of Leuven, Leuven, Belgium. Electronic address: paul.declerck@kuleuven.be. (5) Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven - University of Leuven, Leuven, Belgium. Electronic address: kevin.hollevoet@kuleuven.be.

Covalent Immune Recruiters (CIRs): Tools To Gain Chemical Control Over Immune Recognition

Unprecedented progress made in the treatment of cancer using the body's own immune system has encouraged the development of synthetic molecule based immunotherapeutics. An emerging class of these compounds, called Antibody Recruiting Molecules (ARMs) or Antibody Engagers (AEs), function by reversibly binding antibodies naturally present in human serum and recruiting these to cancer cells to form quaternary complexes with immune cells that drive cancer cell destruction. Despite their promise, the requirement to form quaternary complexes governed by multiple equilibria complicates an understanding of their in vivo efficacy. Particularly problematic are low endogenous serum antibody concentrations and rapid clearance of AEs from circulation. Here we describe a new class of bifunctional chemical tools we call covalent immune recruiters (CIRs). CIRs covalently label specific serum antibodies in a selective manner to a target protein binding ligand. CIRs thereby exert well defined control over antibody recruitment, simply quaternary complex equilibium, and so enable probing resultant effects on immune recognition. We demonstrate CIRs can selectively covalently label anti-DNP IgG, a natural human antibody directly in human serum to drive efficient immune cell recognition of targets. We expect CIRs will be useful tools to probe how quaternary complex stability impacts the immune recognition of cancer in vivo, revealing new design principles to guide the development of future AEs.

Author Info: (1) (2) (3) (4) (5)

Author Info: (1) (2) (3) (4) (5)

Antibody-coated microstructures for selective isolation of immune cells in blood

Cell isolation from blood is an important process for diagnosing immune diseases. There are still demands for a user-friendly approach to achieve high cell extraction efficiency and purity of a target immune cell subtype for more promising diagnosis and monitoring. For selective immune cell isolation, we developed a microstructured device, which consists of antibody-coated micropillars and micro-sieve arrays, for isolating a target immune cell subtype from bovine blood samples. The focusing micropillars can guide immune cells flowing to the subsequent micro-sieves based on deterministic lateral shifts of the cells. The arrangement of these microstructures is characterized and configured for the maximal cell capture rate. Surface modification with a selected antibody offers selective cell capture in the micro-sieves based on the antigen-antibody reaction. We prepare a cell mixture of human CD14-expressing leukemia cells (THP-1) and epithelial cells (MDA-MB-231) in diluted blood to characterize the cell isolation operation, with a selective cell isolation yield of >80%, cell purity of approximately 100% and cell viability of >93%. Together, this microstructured device strategy can achieve high-yield selective isolation of immune cells from blood samples and support downstream genetic and biochemical cell analyses, contributing to the medical diagnosis of a broad range of immune diseases.

Author Info: (1) Department of Biomedical Engineering, City University of Hong Kong, Hong Kong. rhwlam@cityu.edu.hk. (2) Department of Biomedical Engineering, City University of Hong Kong, Hong

Author Info: (1) Department of Biomedical Engineering, City University of Hong Kong, Hong Kong. rhwlam@cityu.edu.hk. (2) Department of Biomedical Engineering, City University of Hong Kong, Hong Kong. rhwlam@cityu.edu.hk. (3) Department of Biomedical Engineering, City University of Hong Kong, Hong Kong. rhwlam@cityu.edu.hk. (4) School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore. (5) Department of Biomedical Engineering, City University of Hong Kong, Hong Kong. rhwlam@cityu.edu.hk. (6) Department of Biomedical Engineering, City University of Hong Kong, Hong Kong. rhwlam@cityu.edu.hk. (7) Department of Biomedical Engineering, City University of Hong Kong, Hong Kong. rhwlam@cityu.edu.hk and Centre for Robotics and Automation, City University of Hong Kong, Hong Kong. (8) Department of Economics and Finance, City University of Hong Kong, Hong Kong. (9) Department of Architecture and Civil Engineering, City University of Hong Kong, Hong Kong. (10) School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore. (11) Department of Biomedical Engineering, City University of Hong Kong, Hong Kong. rhwlam@cityu.edu.hk and Centre for Robotics and Automation, City University of Hong Kong, Hong Kong and Centre for Biosystems, Neuroscience, and Nanotechnology, City University of Hong Kong, Hong Kong and City University of Hong Kong Shenzhen Research Institute, Shenzhen, China.

Close Modal

Small change for you. Big change for us!

This Thanksgiving season, show your support for cancer research by donating your change.

In less than a minute, link your credit card with our partner RoundUp App.

Every purchase you make with that card will be rounded up and the change will be donated to ACIR.

All transactions are securely made through Stripe.