Journal Articles

Dynamics in protein translation sustaining T cell preparedness

ABSTRACT: In response to pathogenic threats, naive T cells rapidly transition from a quiescent to an activated state, yet the underlying mechanisms are incompletely understood. Using a pulsed SILAC approach, we investigated the dynamics of mRNA translation kinetics and protein turnover in human naive and activated T cells. Our datasets uncovered that transcription factors maintaining T cell quiescence had constitutively high turnover, which facilitated their depletion following activation. Furthermore, naive T cells maintained a surprisingly large number of idling ribosomes as well as 242 repressed mRNA species and a reservoir of glycolytic enzymes. These components were rapidly engaged following stimulation, promoting an immediate translational and glycolytic switch to ramp up the T cell activation program. Our data elucidate new insights into how T cells maintain a prepared state to mount a rapid immune response, and provide a resource of protein turnover, absolute translation kinetics and protein synthesis rates in T cells (https://www.immunomics.ch).

Author Info: (1) Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland. (2) Institute of Microbiology, ETH Zürich, Zurich, Switzerland. (3) Biozentr

Author Info: (1) Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland. (2) Institute of Microbiology, ETH Zürich, Zurich, Switzerland. (3) Biozentrum, University of Basel, Basel, Switzerland. (4) Experimental Systems Immunology, Max Planck Institute of Biochemistry, Munich, Germany. (5) Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany. (6) Integrated Research Training Group (IRTG) Medical Epigenetics, Collaborative Research Centre 992, Freiburg, Germany. (7) Institute of Innate Immunity, Department of Systems Immunology and Proteomics, Medical Faculty, University of Bonn, Bonn, Germany. (8) DZIF - German Center for Infection Research, Satellite Center Freiburg, Freiburg, Germany. (9) CIBSS - Centre for Integrative Biological Signalling Studies, Albert-Ludwigs University, Freiburg, Germany. (10) RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, Germany (11) Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Munich, Germany. (12) Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland. roger.geiger@irb.usi.ch.

Versatile chimeric antigen receptor platform for controllable and combinatorial T cell therapy

ABSTRACT: Chimeric antigen receptor (CAR) T cells show remarkable therapeutic effects in some hematological malignancies. However, CAR T cells can also cause life-threatening side effects. In order to minimize off- target and on-target/off-tumor reactions, improve safety, enable controllability, provide high flexibility, and increase tumor specificity, we established a novel humanized artificial receptor platform termed RevCARs. RevCAR genes encode for small surface receptors lacking any antigen-binding moiety. Steering of RevCAR T cells occurs via bispecific targeting molecules (TMs). The small size of RevCAR-encoding genes allows the construction of polycistronic vectors. Here, we demonstrate that RevCAR T cells effi- ciently kill tumor cells, can be steered by TMs, flexibly redirected against multiple targets, and used for combinatorial targeting following the “OR” and “AND” gate logic.

Author Info: (a) Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany; (b) Department of Biophysics and

Author Info: (a) Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany; (b) Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary; (c) Tumor Immunology, University Cancer Center (UCC), University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany; (d) Department of Neurology, Center of Clinical Neuroscience, University Hospital Carl Gustav Carus Dresden, Dresden, Germany; (e) National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; (f) German Cancer Research Center (DKFZ), Heidelberg, Germany; (g) German Cancer Consortium (DKTK), Dresden, Germany.

Single-cell transcriptomics identifies multiple pathways underlying antitumor function of TCR- and CD8αβ-engineered human CD4+ T cells

Rath and Bajwa et al. redirected human T cells by transgenic expression of TCR8, which encodes the co-receptor CD8αβ, and an MHC-I-restricted tumor-associated antigen (TAA)-specific TCR, or only the TCR. TCR8+CD4+, TCR8+CD8+ and TCR+CD8+ (but not TCR+CD4+) T cells acted comparably upon bulk coculture with TAA+ cells. Yet, single-cell analyses showed that TCR8+CD4+ T cells best sustained upregulated expression of the most numerous and diverse sets of genes underlying proliferative, cytolytic, costimulatory, cell cycle, and metabolic pathways, representing a less differentiated and less exhausted profile, and better controlled a leukemia xenograft in vivo.

Contributed by Paula Hochman

Rath and Bajwa et al. redirected human T cells by transgenic expression of TCR8, which encodes the co-receptor CD8αβ, and an MHC-I-restricted tumor-associated antigen (TAA)-specific TCR, or only the TCR. TCR8+CD4+, TCR8+CD8+ and TCR+CD8+ (but not TCR+CD4+) T cells acted comparably upon bulk coculture with TAA+ cells. Yet, single-cell analyses showed that TCR8+CD4+ T cells best sustained upregulated expression of the most numerous and diverse sets of genes underlying proliferative, cytolytic, costimulatory, cell cycle, and metabolic pathways, representing a less differentiated and less exhausted profile, and better controlled a leukemia xenograft in vivo.

Contributed by Paula Hochman

ABSTRACT: Transgenic coexpression of a class I–restricted tumor antigen–specific T cell receptor (TCR) and CD8 (TCR8) redirects antigen specificity of CD4+ T cells. Reinforcement of biophysical properties and early TCR signaling explain how redirected CD4+ T cells recognize target cells, but the transcriptional basis for their acquired antitumor function remains elusive. We, therefore, interrogated redirected human CD4+ and CD8+ T cells by single-cell RNA sequencing and characterized them experimentally in bulk and single-cell assays and a mouse xenograft model. TCR8 expression enhanced CD8+ T cell function and preserved less differentiated CD4+ and CD8+ T cells after tumor challenge. TCR8+ CD4+ T cells were most potent by activating multiple transcriptional programs associated with enhanced antitumor function. We found sustained activation of cytotoxicity, costimulation, oxidative phosphorylation– and proliferation-related genes, and simultaneously reduced differentiation and exhaustion. Our study identifies molecular features of TCR8 expression that can guide the development of enhanced immunotherapies.

Author Info: (1) Department of Oncology UNIL-CHUV, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland. (2) Center for Cell and Gen

Author Info: (1) Department of Oncology UNIL-CHUV, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland. (2) Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children’s Hospital, Houston, TX, USA. (3) Department of Chemical and Biomolecular Engineering, University of Houston, TX, USA. (4) Biostatistics Shared Resource, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. (5) Department of Medicine, Baylor College of Medicine, Houston, TX, USA. (6) Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. (7) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Identification of human CD4+ T cell populations with distinct antitumor activity

Nelson and Knochelmann et al. report that CD26high CD4+ T cells represent a distinct population of CD4+ helper T cells with potent antitumor properties. CD26high CD4+ T cells differ from TH1, TH2, and TH17 cells based on surface markers, increased cytokine production (IL-17, IFNγ, IL-22, and IL-2), epigenetic landscape, and gene expression patterns. CD26high CD4+ T cells expressing first generation mesothelin-specific CAR increased CD4+ and CD8+ CAR T cell persistence in vivo, eradicated large established mesothelioma tumors, and increased survival  independent of IL-17 and CD26 expression and of CD8+ CAR T cells.

Contributed by Shishir Pant

Nelson and Knochelmann et al. report that CD26high CD4+ T cells represent a distinct population of CD4+ helper T cells with potent antitumor properties. CD26high CD4+ T cells differ from TH1, TH2, and TH17 cells based on surface markers, increased cytokine production (IL-17, IFNγ, IL-22, and IL-2), epigenetic landscape, and gene expression patterns. CD26high CD4+ T cells expressing first generation mesothelin-specific CAR increased CD4+ and CD8+ CAR T cell persistence in vivo, eradicated large established mesothelioma tumors, and increased survival  independent of IL-17 and CD26 expression and of CD8+ CAR T cells.

Contributed by Shishir Pant

ABSTRACT: How naturally arising human CD4+ T helper subsets affect cancer immunotherapy is unclear. We reported that human CD4+CD26high T cells elicit potent immunity against solid tumors. As CD26high T cells are often categorized as TH17 cells for their IL-17 production and high CD26 expression, we posited these populations would have similar molecular properties. Here, we reveal that CD26high T cells are epigenetically and transcriptionally distinct from TH17 cells. Of clinical importance, CD26high and TH17 cells engineered with a chimeric antigen receptor (CAR) regressed large human tumors to a greater extent than enriched TH1 or TH2 cells. Only human CD26high T cells mediated curative responses, even when redirected with a suboptimal CAR and without aid by CD8+ CAR T cells. CD26high T cells cosecreted effector cytokines, produced cytotoxic molecules, and persisted long term. Collectively, our work underscores the promise of CD4+ T cell populations to improve durability of solid tumor therapies.

Author Info: (1) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA. (2) Department of Dermatology and Dermatologic Surgery, Medical University

Author Info: (1) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA. (2) Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, SC, USA. (3) Department of Surgery, Medical University of South Carolina, Charleston, SC, USA. (4) Department of Surgery, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA. (5) Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA. (6) Epinomics, Menlo Park, CA, USA. (7) Department of Public Health Sciences, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA. (8) Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.

Structural cells are key regulators of organ-specific immune responses

Krausgruber and Fortelny et al. isolated structural cells (i.e. epithelium, endothelium, and fibroblasts) from 12 mouse organs, observing cell type and organ-specific differences in expression and transcriptional regulation of immune-related genes. In homeostasis, immune interaction molecules and secreted factors were widely expressed in structural cells and varied more strongly between organs than between cell types in the same organ. Genes with low expression but high chromatin accessibility were enriched in immune interactors and indicated epigenetic potential for upregulation, confirmed in viral infection or cytokine treatment.

Contributed by Alex Najibi

Krausgruber and Fortelny et al. isolated structural cells (i.e. epithelium, endothelium, and fibroblasts) from 12 mouse organs, observing cell type and organ-specific differences in expression and transcriptional regulation of immune-related genes. In homeostasis, immune interaction molecules and secreted factors were widely expressed in structural cells and varied more strongly between organs than between cell types in the same organ. Genes with low expression but high chromatin accessibility were enriched in immune interactors and indicated epigenetic potential for upregulation, confirmed in viral infection or cytokine treatment.

Contributed by Alex Najibi

ABSTRACT: The mammalian immune system implements a remarkably effective set of mechanisms for fighting pathogens1. Its main components are haematopoietic immune cells, including myeloid cells that control innate immunity, and lymphoid cells that constitute adaptive immunity2. However, immune functions are not unique to haematopoietic cells, and many other cell types display basic mechanisms of pathogen defence3-5. To advance our understanding of immunology outside the haematopoietic system, here we systematically investigate the regulation of immune genes in the three major types of structural cells: epithelium, endothelium and fibroblasts. We characterize these cell types across twelve organs in mice, using cellular phenotyping, transcriptome sequencing, chromatin accessibility profiling and epigenome mapping. This comprehensive dataset revealed complex immune gene activity and regulation in structural cells. The observed patterns were highly organ-specific and seem to modulate the extensive interactions between structural cells and haematopoietic immune cells. Moreover, we identified an epigenetically encoded immune potential in structural cells under tissue homeostasis, which was triggered in response to systemic viral infection. This study highlights the prevalence and organ-specific complexity of immune gene activity in non-haematopoietic structural cells, and it provides a high-resolution, multi-omics atlas of the epigenetic and transcriptional networks that regulate structural cells in the mouse.

Author Info: (1) CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. (2) Division of Chromatin Networks, German Cancer Research Center (DKFZ) and B

Author Info: (1) CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. (2) Division of Chromatin Networks, German Cancer Research Center (DKFZ) and Bioquant, Heidelberg, Germany. (3) Regensburg Center for Interventional Immunology (RCI), Regensburg, Germany. (4) CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. cbock@cemm.oeaw.ac.at. (5) Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria. cbock@cemm.oeaw.ac.at.

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-beta and PD-L1, in advanced squamous cell carcinoma of the head and neck: results from a phase I cohort

BACKGROUND: We report the clinical activity and safety of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor beta (TGF-beta)RII receptor (a TGF-beta 'trap') fused to a human IgG1 monoclonal antibody blocking programmed death-ligand 1 (PD-L1), in patients with heavily pretreated squamous cell carcinoma of the head and neck (SCCHN). METHODS: In this phase I dose-expansion cohort, patients with advanced SCCHN not amenable to curative therapy that progressed/recurred after platinum therapy in the recurrent/metastatic setting, or <6 months after platinum therapy in the locally advanced setting, received bintrafusp alfa 1200 mg intravenously every 2 weeks. The primary endpoint was confirmed best overall response (BOR; Response Evaluation Criteria for Solid Tumors (RECIST) 1.1) per independent review committee (IRC); other endpoints included BOR per investigator and safety. RESULTS: As of August 24, 2018, 32 patients had received bintrafusp alfa (median follow-up 86.4 weeks; range 2-97). Per IRC, the confirmed objective response rate (ORR) was 13% (95% CI 4% to 29%; 4 partial responses (PR)); 4 patients had stable disease (SD) (disease control rate 25%; 95% CI 12% to 43%). Per investigator, there were 5 PRs (ORR, 16%), including 2 patients who developed delayed PRs after initial disease increase (total clinical response rate 22%). Responses (ORRs) were observed in patients with PD-L1-positive (12%), PD-L1-negative (17%; 73-10 antibody for immunohistochemistry), human papillomavirus (HPV)-positive (33%) and HPV-negative tumors (5%). Grade 3 treatment-related adverse events (TRAEs) were reported in 11 patients (34%), with no grade 4 TRAEs or treatment-related deaths. CONCLUSIONS: Bintrafusp alfa showed clinical activity across subgroups of PD-L1 expression and in HPV-positive tumors and had a manageable safety profile in patients with heavily pretreated advanced SCCHN. Activity in HPV-positive tumors is favorable compared with historical data from PD-L1 inhibitors and is being further investigated in an ongoing study of HPV-associated tumors. TRIAL REGISTRATION NUMBER: NCT02517398.

Author Info: (1) Department of Internal Medicine, Yonsei University College of Medicine, Seoul, The Republic of Korea cbc1971@yuhs.ac. (2) Department of Medical Oncology, Hopital Saint-Andre, U

Author Info: (1) Department of Internal Medicine, Yonsei University College of Medicine, Seoul, The Republic of Korea cbc1971@yuhs.ac. (2) Department of Medical Oncology, Hopital Saint-Andre, University of Bordeaux-CHU, Bordeaux, France. (3) Department of Medical Oncology, Hopital Saint-Andre, University of Bordeaux-CHU, Bordeaux, France. (4) CEPCM Assistance Publique des Hopitaux de Marseille, Aix-Marseille Universite, Marseille, France. (5) Service d'Oncologie medicale, CLCC Georges-Francois Leclerc, Dijon Cedex, France. (6) Institute for Melanoma Research & Education, California Cancer Associates for Research & Excellence, Encinitas, California, USA. (7) Department of Oncology Medicine, Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium. (8) Service d'Oncologie medicale, CLCC Paul Strauss, Strasbourg, France. (9) EMD Serono Research & Development Institute, Billerica, Massachusetts, USA. (10) Merck KGaA, Darmstadt, Germany. (11) EMD Serono Research & Development Institute, Billerica, Massachusetts, USA. (12) Genitourinary Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. (13) Department of Medical Oncology, Centre Oscar Lambret and Lille University Hospital, Lille, France.

Harnessing NK Cell Checkpoint-Modulating Immunotherapies

During the host immune response, the precise balance of the immune system, regulated by immune checkpoint, is required to avoid infection and cancer. These immune checkpoints are the mainstream regulator of the immune response and are crucial for self-tolerance. During the last decade, various new immune checkpoint molecules have been studied, providing an attractive path to evaluate their potential role as targets for effective therapeutic interventions. Checkpoint inhibitors have mainly been explored in T cells until now, but natural killer (NK) cells are a newly emerging target for the determination of checkpoint molecules. Simultaneously, an increasing number of therapeutic dimensions have been explored, including modulatory and inhibitory checkpoint molecules, either causing dysfunction or promoting effector functions. Furthermore, the combination of the immune checkpoint with other NK cell-based therapeutic strategies could also strengthen its efficacy as an antitumor therapy. In this review, we have undertaken a comprehensive review of the literature to date regarding underlying mechanisms of modulatory and inhibitory checkpoint molecules.

Author Info: (1) Institute of cellular therapeutics, Hannover Medical School, 30625 Hannover, Germany. (2) Institute of cellular therapeutics, Hannover Medical School, 30625 Hannover, Germany.

Author Info: (1) Institute of cellular therapeutics, Hannover Medical School, 30625 Hannover, Germany. (2) Institute of cellular therapeutics, Hannover Medical School, 30625 Hannover, Germany. Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany. Institute of Clinical Immunology, University of Leipzig, 04103 Leipzig, Germany. (3) Institute of cellular therapeutics, Hannover Medical School, 30625 Hannover, Germany.

Tumors Resistant to Checkpoint Inhibitors Can Become Sensitive after Treatment with Vascular Disrupting Agents

Immune therapy improves cancer outcomes, yet many patients do not respond. This pre-clinical study investigated whether vascular disrupting agents (VDAs) could convert an immune unresponsive tumor into a responder. CDF1 mice, with 200 mm(3) C3H mammary carcinomas in the right rear foot, were intraperitoneally injected with combretastatin A-4 phosphate (CA4P), its A-1 analogue OXi4503, and/or checkpoint inhibitors (anti-PD-1, PD-L1, or CTLA-4 antibodies), administered twice weekly for two weeks. Using the endpoint of tumor growth time (TGT5; time to reach five times the starting volume), we found that none of the checkpoint inhibitors (10 mg/kg) had any effect on TGT5 compared to untreated controls. However, CA4P (100 mg/kg) or OXi4503 (5-50 mg/kg) did significantly increase TGT5. This further significantly increased by combining the VDAs with checkpoint inhibitors, but was dependent on the VDA, drug dose, and inhibitor. For CA4P, a significant increase was found when CA4P (100 mg/kg) was combined with anti-PD-L1, but not with the other two checkpoint inhibitors. With OXi4503 (50 mg/kg), a significant enhancement occurred when combined with anti-PD-L1 or anti-CTLA-4, but not anti-PD-1. We observed no significant improvement with lower OXi4503 doses (5-25 mg/kg) and anti-CTLA-4, although 30% of tumors were controlled at the 25 mg/kg dose. Histological assessment of CD4/CD8 expression actually showed decreased levels up to 10 days after treatment with OXi4503 (50 mg/kg). Thus, the non-immunogenic C3H mammary carcinoma was unresponsive to checkpoint inhibitors, but became responsive in mice treated with VDAs, although the mechanism remains unclear.

Author Info: (1) Experimental Clinical Oncology-Department of Oncology, Aarhus University Hospital, DK-8200 Aarhus, Denmark. (2) Experimental Clinical Oncology-Department of Oncology, Aarhus Un

Author Info: (1) Experimental Clinical Oncology-Department of Oncology, Aarhus University Hospital, DK-8200 Aarhus, Denmark. (2) Experimental Clinical Oncology-Department of Oncology, Aarhus University Hospital, DK-8200 Aarhus, Denmark. (3) Department of Pathology, Aarhus University Hospital, DK-8200 Aarhus, Denmark. (4) Experimental Clinical Oncology-Department of Oncology, Aarhus University Hospital, DK-8200 Aarhus, Denmark.

Lignin nanoparticles as a promising vaccine adjuvant and delivery system for ovalbumin

Vaccination is the most effective strategy of preventing and treating infectious diseases and the most significant issue in the development of potent vaccines is the sufficient immunogenicity and safety of vaccines. The main goal of the present study is to develop a potent and safe vaccine adjuvant that can also stabilize antigen formulations during preparation and storage. In this study, the model antigen ovalbumin (OVA) was encapsulated in polymeric nanoparticles based on lignin (OVA-LNPs). The nanoparticles had a particle size of 216nm and a low polydispersity index. The nanoparticles were negatively charged (-26.7mV) with high encapsulation efficiency 81.6% of OVA antigen. In vitro studies of the nanoparticles were tested against dendritic cells (DCs), specialized antigen-presenting cells (APCs). The results showed no cytotoxic effect from LNPs and a significantly higher percentage of dendritic cells have taken up the antigen when encapsulated inside LNPs in contrast to free OVA. The nanoparticle was administered intradermally to BALB/c mice and the resulting time-dependent systemic immune responses towards OVA were assessed by measuring the OVA-specific IgG titers using an enzyme-linked immunosorbent assay (ELISA). In vivo immunization with OVA-LNPs induced a stronger IgG antibody response than that induced by free OVA or alum adjuvanted OVA. Enhanced immunization by OVA-LNPs was attributed to the observed efficient uptake of the antigen by dendritic cells. These findings demonstrate that LNPs are promising to be used as vaccine adjuvant and delivery system for the induction of long-term immune responses.

Author Info: (1) Department of Pharmaceutics, College of Pharmacy, PO Box 2457, King Saud University, Riyadh 11451, Saudi Arabia. Electronic address: msaalqahtani@ksu.edu.sa. (2) Department of

Author Info: (1) Department of Pharmaceutics, College of Pharmacy, PO Box 2457, King Saud University, Riyadh 11451, Saudi Arabia. Electronic address: msaalqahtani@ksu.edu.sa. (2) Department of Pharmaceutics, College of Pharmacy, PO Box 2457, King Saud University, Riyadh 11451, Saudi Arabia. (3) Department of Pharmacognosy, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia. (4) Department of Pharmaceutics, College of Pharmacy, PO Box 2457, King Saud University, Riyadh 11451, Saudi Arabia. (5) Department of Pharmaceutics, College of Pharmacy, PO Box 2457, King Saud University, Riyadh 11451, Saudi Arabia. (6) Department of Pharmaceutics, College of Pharmacy, PO Box 2457, King Saud University, Riyadh 11451, Saudi Arabia.

Delivery strategies for macromolecular drugs in cancer therapy

With the development of biotherapy, biomacromolecular drugs have gained tremendous attention recently, especially in drug development field due to the sophisticated functions in vivo. Over the past few years, a motley variety of drug delivery strategies have been developed for biomacromolecular drugs to overcome the difficulties in the druggability, e.g., the instability and easily restricted by physiologic barriers. The application of novel delivery systems to deliver biomacromolecular drugs can usually prolong the half-life, increase the bioavailability, or improve patient compliance, which greatly improves the efficacy and potentiality for clinical use of biomacromolecular drugs. In this review, recent studies regarding the drug delivery strategies for macromolecular drugs in cancer therapy are summarized, mainly drawing on the development over the last five years.

Author Info: (1) Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, S

Author Info: (1) Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China. (2) Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China.

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