scholarly journals Dynamic Covalent Dextran Hydrogels as Injectable, Self-adjuvating Peptide Vaccine Depots

2021 ◽  
Author(s):  
Bowen Fan ◽  
Diana Torres Garcia ◽  
Marziye Salehi ◽  
Sander van Kasteren ◽  
Rienk Eelkema
Keyword(s):  
Drug Delivery ◽  
T Cells ◽  
Cell Therapy ◽  
Tissue Regeneration ◽  
Peptide Vaccine ◽  
Therapeutic Agents ◽  
Self Healing ◽  
Peptide Vaccines ◽  
Peptide Antigen ◽  
Covalent Crosslinks

Dextran-based hydrogels are promising therapeutic materials for drug delivery, tissue regeneration devices, and cell therapy vectors, due to their high biocompatibility, along with their ability to protect and release active therapeutic agents. This report describes the synthesis, characterization and application of a new dynamic covalent dextran hydrogel as an injectable depot for peptide vaccines. Dynamic covalent crosslinks based on double Michael addition of thiols to alkynones impart the dextran hydrogel with shear-thinning and self-healing capabilities, enabling hydrogel injection. These injectable, non-toxic hydrogels show adjuvant potential and have predictable sub-millimolar loading and release of the peptide antigen SIINFEKL, which after its release is able to activate T-cells, demonstrating that the hydrogels deliver peptides without modifying their immunogenicity. This work demonstrates the potential of dynamic covalent dextran hydrogels as a sustained-release material for delivery of peptide vaccines.

scholarly journals 611 Exploiting T cells as vehicles of liposomal SHP2i to enhance adoptive cell therapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A641-A641
Author(s):  
Xin Li ◽  
Hólmfridur Halldórsdóttir ◽  
Sven Weller ◽  
Anna Colliander ◽  
Ditte Jæhger ◽  
...  
Keyword(s):  
Drug Delivery ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cell Viability ◽  
Cancer Immunotherapy ◽  
Lipid Nanoparticles ◽  
Immunomodulatory Drugs ◽  
Cell Loading

BackgroundAdoptive T cell therapy (ACT) is often accompanied by supporting immunomodulatory drugs to protect T cells from the suppressive tumor microenvironment (TME) [1]. However, systemic administration of these immunomodulators can cause serious side effects and fail to distribute optimally to exert sufficient lymphocyte stimulation within the tumor and lymphoid compartments. Loading T cells with adjuvant drugs or cytokines prior to cell transfer provides a solution to this issue, showing the potential to use T cells as vehicles to carry immunomodulatory molecules to target sites [2]. SHP2 is an important hub connecting several intracellular oncogenic signaling pathways including PD-1/PD-L1, representing a notable target for cancer immunotherapy. SHP2 inhibition has been shown to elicited tumor regression by improving CD8+ T cells activity [3]. Herein we present a lipid nanoparticle system encapsulating an SHP2 inhibitor (SHP2i) that allows high T cell loading capacity and enhances their therapeutic activity.MethodsRemote-loading gradients were used to achieve high encapsulation efficiency of SHP2i into the lipid nanoparticle platform. Mouse cytotoxic T cells were loaded with SHP2i, and loading efficiency and release rates from the T cells were evaluated in vitro. Flow cytometry was used to assess T cell viability, proliferation, and phenotype. In vivo biodistribution of loaded T cells was evaluated by labeling lipid nanoparticles with gadolinium and T cells with Cell-trace-marker, which were measured with ICP-MS and Flow respectively. The therapeutic anti-tumor efficacy of the loaded T cells was demonstrated on EG.7-OVA tumor-bearing mice.ResultsThe developed formulation allowed high T cell loading efficiency of SHPi and extended-release over 5 days. Loading T cells with lipid formulated SHP2i did not compromise cell viability and proliferation and resulted in T cells retaining a central memory phenotype than unloaded counterparts. Adoptively transferred T cells loaded with lipid nanoparticles showed the same distribution and proliferation behavior as the unloaded T cells in vivo, accumulating into tumor tissue three days post cell infusion. Loaded OT.I T cells significantly improved tumor growth inhibition and overall survival than OT.I T cells alone, with 5 out of 6 mice completely tumor-free, resulting in durable long-term responders.ConclusionsLoading T cells with liposomal SHP2i before ACT allowed specific and controlled delivery of immunomodulatory drugs by T cells. The loaded T cells showed improved anti-tumor efficacy. The developed lipid formulation allows the loading of a variety of immunomodulatory drugs to T cells, which serve both as a drug delivery vehicle and enhance the tumor efficacy of the transferred cells.ReferencesWaldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat. Rev. Immunol. 2020. p. 651–68.Combes F, Meyer E, Sanders NN. Immune cells as tumor drug delivery vehicles. J Control Release. Elsevier; 2020;327:70–87.Yuan X, Bu H, Zhou J, Yang CY, Zhang H. Recent Advances of SHP2 Inhibitors in Cancer Therapy: Current Development and Clinical Application. J Med Chem. 2020;63:11368–96.Ethics ApprovalThe study has been approved by the Danish Animal Experiments Inspectorate with the permit number 2020-15-0201-00482. The participants gave informed consent before taking part.

scholarly journals Electroactive biomaterials: Vehicles for controlled delivery of therapeutic agents for drug delivery and tissue regeneration

2018 ◽  
Vol 129 ◽  
pp. 148-168 ◽  
Author(s):  
Biranche Tandon ◽  
Adrián Magaz ◽  
Richard Balint ◽  
Jonny J. Blaker ◽  
Sarah H. Cartmell
Keyword(s):  
Drug Delivery ◽  
Tissue Regeneration ◽  
Therapeutic Agents ◽  
Controlled Delivery

The Potential of Fucose-Containing Sulfated Polysaccharides As Scaffolds for Biomedical Applications

2019 ◽  
Vol 26 (35) ◽  
pp. 6399-6411 ◽  
Author(s):  
Cláudia Nunes ◽  
Manuel A. Coimbra
Keyword(s):  
Tissue Regeneration ◽  
Cell Walls ◽  
Biomedical Applications ◽  
Structural Features ◽  
Therapeutic Agents ◽  
Sulfated Polysaccharides ◽  
Clinical Use ◽  
Health Related ◽  
Pathogen Inhibition ◽  
Health Applications

Marine environments have a high quantity and diversity of sulfated polysaccharides. In coastal regions brown algae are the most abundant biomass producers and their cell walls have fucosecontaining sulfated polysaccharides (FCSP), known as fucans and/or fucoidans. These sulfated compounds have been widely researched for their biomedical properties, namely the immunomodulatory, haemostasis, pathogen inhibition, anti-inflammatory capacity, and antitumoral. These activities are probably due to their ability to mimic the carbohydrate moieties of mammalian glycosaminoglycans. Therefore, the FCSP are interesting compounds for application in health-related subjects, mainly for developing scaffolds for delivery systems or tissue regeneration. FCSP showed potential for these applications also due to their ability to form stable 3D structures with other polymers able to entrap therapeutic agents or cell and growth factors, besides their biocompatibility and biodegradability. However, for the clinical use of these biopolymers well-defined reproducible molecules are required in order to accurately establish relationships between structural features and human health applications.

Bridging the Gap of Drug Delivery in Colon Cancer: The Role of Chitosan and Pectin Based Nanocarriers System

2020 ◽  
Vol 17 (10) ◽  
pp. 911-924
Author(s):  
Rohitas Deshmukh
Keyword(s):  
Drug Delivery ◽  
Colon Cancer ◽  
Targeted Drug Delivery ◽  
Targeted Delivery ◽  
Therapeutic Agent ◽  
Therapeutic Agents ◽  
Delivery Systems ◽  
Target Tissue ◽  
Polymer Carriers

Colon cancer is one of the most prevalent diseases, and traditional chemotherapy has not been proven beneficial in its treatment. It ranks second in terms of mortality due to all cancers for all ages. Lack of selectivity and poor biodistribution are the biggest challenges in developing potential therapeutic agents for the treatment of colon cancer. Nanoparticles hold enormous prospects as an effective drug delivery system. The delivery systems employing the use of polymers, such as chitosan and pectin as carrier molecules, ensure the maximum absorption of the drug, reduce unwanted side effects and also offer protection to the therapeutic agent from quick clearance or degradation, thus allowing an increased amount of the drug to reach the target tissue or cells. In this systematic review of published literature, the author aimed to assess the role of chitosan and pectin as polymer-carriers in colon targeted delivery of drugs in colon cancer therapy. This review summarizes the various studies employing the use of chitosan and pectin in colon targeted drug delivery systems.

Heat Stress and Pulsed Unfocused Ultrasound: The Viability of these Physical Approaches for Drug Delivery into Testicular Seminiferous Tubules

2020 ◽  
Vol 17 (5) ◽  
pp. 438-446 ◽  
Author(s):  
Yuanyuan Li ◽  
Mohammad Ishraq Zafar ◽  
Xiaotong Wang ◽  
Xiaofang Ding ◽  
Honggang Li
Keyword(s):  
Drug Delivery ◽  
Heat Stress ◽  
Targeted Drug Delivery ◽  
Therapeutic Agents ◽  
Seminiferous Tubules ◽  
Adult Mice ◽  
Targeted Drug ◽  
To Receive ◽  
Unfocused Ultrasound ◽  
Blood Testis Barrier

Aim: To investigate the application of Scrotal Heat Stress (SHS) and Pulsed Unfocused Ultrasound (PuFUS) to explore Blood-Testis Barrier (BTB) permeability in adult mice. Background: The BTB provides a stable microenvironment and a unique immune barrier for spermatogenesis. Meanwhile, it blocks macromolecular substances access, including therapeutic agents and antibodies, thereby it decreases the therapeutic or immunocontraception effects. Objectives: To determine the viability of these physical approaches in delivering macromolecular substances into seminiferous tubules. Material & Methods: Mice were subjected to receive single SHS intervention at 39°C, 41°C, or 43°C for 30 min. Whereas, mice received the PuFUS intervention at 1.75w/cm2, 1.25w/cm2, and 2.5w/cm2 for 2 min, 5 min, and 10 min, respectively. The Biotin and macromolecular substances (IgG, IgM, and exosomes) were separately injected into the testicular interstitium at different times following SHS or PuFUS interventions, to observe their penetration through BTB into seminiferous tubules. Results: As detected by Biotin tracer, the BTB opening started from day-2 following the SHS and lasted for more than three days, whereas the BTB opening started from 1.5h following PuFUS and lasted up to 24h. Apparent penetration of IgG, IgM, and exosomes into seminiferous tubules was observed after five days of the SHS at 43°C, but none at 39°C, or any conditions tested with PuFUS. Conclusion: The current results indicate that SHS at 43°C comparatively has the potential for delivering macromolecular substances into seminiferous tubules, whereas the PuFUS could be a novel, quick, and mild approach to open the BTB. These strategies might be useful for targeted drug delivery into testicular seminiferous tubules. However, further studies are warranted to validate our findings.

scholarly journals Anti-Mesothelin CAR T cell therapy for malignant mesothelioma

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Laura Castelletti ◽  
Dannel Yeo ◽  
Nico van Zandwijk ◽  
John E. J. Rasko
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Malignant Mesothelioma ◽  
Oncolytic Viruses ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

AbstractMalignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a novel potential treatment for this incurable solid tumor. The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in MM, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of MM patients and not (or very modestly) present in healthy tissues. Clinical trials using anti-MSLN CAR T cells in MM have shown that this potential therapeutic is relatively safe. However, efficacy remains modest, likely due to the MM tumor microenvironment (TME), which creates strong immunosuppressive conditions and thus reduces anti-MSLN CAR T cell tumor infiltration, efficacy and persistence. Various approaches to overcome these challenges are reviewed here. They include local (intratumoral) delivery of anti-MSLN CAR T cells, improved CAR design and co-stimulation, and measures to avoid T cell exhaustion. Combination therapies with checkpoint inhibitors as well as oncolytic viruses are also discussed. Preclinical studies have confirmed that increased efficacy of anti-MSLN CAR T cells is within reach and offer hope that this form of cellular immunotherapy may soon improve the prognosis of MM patients.

773 Adoptive Cell Therapy Response in Melanoma is Mediated by Stem-like CD8 T cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A822-A822
Author(s):  
Sri Krishna ◽  
Frank Lowery ◽  
Amy Copeland ◽  
Stephanie Goff ◽  
Grégoire Altan-Bonnet ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Single Cell ◽  
Cd8 T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
High Dimensional ◽  
Tumor Control ◽  
Intrinsic Factors ◽  
Infiltrating Lymphocytes

BackgroundAdoptive T cell therapy (ACT) utilizing ex vivo-expanded autologous tumor infiltrating lymphocytes (TILs) can result in complete regression of human cancers.1 Successful immunotherapy is influenced by several tumor-intrinsic factors.2 3 Recently, T cell-intrinsic factors have been associated with immunotherapy response in murine and human studies.4 5 Analyses of tumor-reactive TILs have concluded that anti-tumor neoantigen-specific TILs are enriched in subsets defined by the expression of PD-1 or CD39.6 7 Thus, there is a lack of consensus regarding the tumor-reactive TIL subset that is directly responsible for successful immunotherapies such as ICB and ACT. In this study, we attempted to define the fitness landscape of TIL-enriched infusion products to specifically understand its phenotypic impact on human immunotherapy responses.MethodsWe compared the phenotypic differences that could distinguish bulk ACT infusion products (I.P.) administered to patients who had complete response to therapy (complete responders, CRs, N = 24) from those whose disease progressed following ACT (non-responders, NRs, N = 30) by high dimensional single cell protein and RNA analysis of the I.P. We further analyzed the phenotypic states of anti-tumor neoantigen specific TILs from patient I.P (N = 26) by flow cytometry and single cell transcriptomics.ResultsWe identified two CD8+ TIL populations associated with clinical outcomes: a memory-progenitor CD39-negative stem-like TIL (CD39-CD69-) in the I.P. associated with complete cancer regression (overall survival, P < 0.0001, HR = 0.217, 95% CI 0.101 to 0.463) and TIL persistence, and a terminally differentiated CD39-positive TIL (CD39+CD69+) population associated with poor TIL persistence post-treatment. Although the majority (>65%) of neoantigen-reactive TILs in both responders and non-responders to ACT were found in the differentiated CD39+ state, CR infusion products also contained a pool of CD39- stem-like neoantigen-specific TILs (median = 8.8%) that was lacking in NR infusion products (median = 23.6%, P = 1.86 x 10-5). Tumor-reactive stem-like T cells were capable of self-renewal, expansion, and persistence, and mediated superior anti-tumor response in vivo.ConclusionsOur results support the hypothesis that responders to ACT received infusion products containing a pool of stem-like neoantigen-specific TILs that are able to undergo prolific expansion, give rise to differentiated subsets, and mediate long-term tumor control and T cell persistence, in line with recent murine ICB studies mediated by TCF+ progenitor T cells.4 5 Our data also suggest that TIL subsets mediating ACT-response (stem-like CD39-) might be distinct from TIL subsets enriched for anti-tumor-reactivity (terminally differentiated CD39+) in human TIL.6 7AcknowledgementsWe thank Don White for curating the melanoma patient cohort, and J. Panopoulos (Flowjo) for helpful discussions on high-dimensional analysis, and NCI Surgery Branch members for helpful insights and suggestions. S. Krishna acknowledges funding support from NCI Director’s Innovation Award from the National Cancer Institute.Trial RegistrationNAEthics ApprovalThe study was approved by NCI’s IRB ethics board.ReferencesGoff SL, et al. Randomized, prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma. J Clin Oncol 2016;34:2389–2397.Snyder A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014;371:2189–2199.McGranahan N, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016;351:1463–1469.Sade-Feldman M, et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 2019;176:404.Miller BC, et al. Subsets of exhausted CD8 T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol 2019;20:326–336.Simoni Y, et al. Bystander CD8 T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 2018;557:575–579.Gros A, et al. PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors. J Clin Invest 2014;124:2246–2259.

scholarly journals Concomitant control of mechanical properties and degradation in resorbable elastomer-like materials using stereochemistry and stoichiometry for soft tissue engineering

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mary Beth Wandel ◽  
Craig A. Bell ◽  
Jiayi Yu ◽  
Maria C. Arno ◽  
Nathan Z. Dreger ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Drug Delivery ◽  
Soft Tissue ◽  
Tissue Regeneration ◽  
Biological Tissues ◽  
Soft Tissue Regeneration ◽  
Soft Tissue Engineering ◽  
Degradation Properties ◽  
Enhance Cell Adhesion

AbstractComplex biological tissues are highly viscoelastic and dynamic. Efforts to repair or replace cartilage, tendon, muscle, and vasculature using materials that facilitate repair and regeneration have been ongoing for decades. However, materials that possess the mechanical, chemical, and resorption characteristics necessary to recapitulate these tissues have been difficult to mimic using synthetic resorbable biomaterials. Herein, we report a series of resorbable elastomer-like materials that are compositionally identical and possess varying ratios of cis:trans double bonds in the backbone. These features afford concomitant control over the mechanical and surface eroding degradation properties of these materials. We show the materials can be functionalized post-polymerization with bioactive species and enhance cell adhesion. Furthermore, an in vivo rat model demonstrates that degradation and resorption are dependent on succinate stoichiometry in the elastomers and the results show limited inflammation highlighting their potential for use in soft tissue regeneration and drug delivery.

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