scholarly journals Targeted Activation of T Cells with IL-2-Coupled Nanoparticles

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2063
Author(s):  
Verena K. Raker ◽  
Christian Becker ◽  
Katharina Landfester ◽  
Kerstin Steinbrink
Keyword(s):  
T Cell ◽  
Inflammatory Diseases ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Drug Binding ◽  
High Dose ◽  
Cell Responses ◽  
Autoimmune And Inflammatory Diseases ◽  
Specific Receptors ◽  
T Cell Growth Factor

Interleukin-2 (IL-2) is a T cell growth factor particularly required in regulatory T cell maintenance and memory T cell responses. High-dose IL-2 treatment was the first FDA-approved immunotherapy for cancer, while low-dose IL-2 administration has shown promise in allograft rejection and autoimmune and inflammatory diseases. However, its pleiotropic nature and the existence of IL-2 receptors with different binding affinity limit its therapeutic application. For an improved clinical applicability of the cytokine, a targeted receptor assignment must, therefore, be achieved. Nanoparticles allow controlling the location and dose of immunomodulating compounds and to specifically address specific receptors through targeted drug binding. In this review article we discuss the IL-2 biology and current clinical application with regard to nanoparticle-based IL-2-mediated manipulation of T cell responses in autoimmunity, chronic inflammation, and cancer.

scholarly journals NKTR-214 immunotherapy synergizes with radiotherapy to stimulate systemic CD8+T cell responses capable of curing multi-focal cancer

2020 ◽  
Vol 8 (1) ◽  
pp. e000464
Author(s):  
Joshua M Walker ◽  
Annah S Rolig ◽  
Deborah H Charych ◽  
Ute Hoch ◽  
Melissa J Kasiewicz ◽  
...  
Keyword(s):  
T Cell ◽  
Combination Therapy ◽  
Antitumor Immunity ◽  
Killer Cell ◽  
Locally Advanced ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
High Dose ◽  
Type I ◽  
Cell Responses

BackgroundHigh-dose radiotherapy (RT) is known to be immunogenic, but is rarely capable of driving clinically relevant abscopal antitumor immunity as monotherapy. RT is known to increase antigen presentation, type I/II interferon responses, and immune cell trafficking to irradiated tumors. Bempegaldesleukin (NKTR-214) is a CD122-preferential interleukin 2 (IL-2) pathway agonist that has been shown to increase tumor-infiltrating lymphocytes, T cell clonality, and increase PD-1 expression. NKTR-214 has increased drug half-life, decreased toxicity, and increased CD8+T cell and natural killer cell stimulation compared with IL-2.MethodsAnimals bearing bilateral subcutaneous MCA-205 fibrosarcoma or CT26 colorectal tumors were treated with NKTR-214, RT, or combination therapy, and tumor growth of irradiated and abscopal lesions was assessed. Focal RT was delivered using a small animal radiation research platform. Peripheral and tumor-infiltrating immune phenotype and functional analyses were performed by flow cytometry. RNA expression profiling from both irradiated and abscopal lesions was performed using microarray.ResultsWe demonstrate synergy between RT of a single tumor and NKTR-214 systemic therapy resulting in dramatically increased cure rates of mice bearing bilateral tumors compared with RT or NKTR-214 therapy alone. Combination therapy resulted in increased magnitude and effector function of tumor-specific CD8+T cell responses and increased trafficking of these T cells to both irradiated and distant, unirradiated, tumors.ConclusionsGiven the increasing role of hypofractionated and stereotactic body RT as standard of care treatments in the management of locally advanced and metastatic cancer, these data have important implications for future clinical trial development. The combination of RT and NKTR-214 therapy potently stimulates systemic antitumor immunity and should be evaluated for the treatment of patients with locally advanced and metastatic solid tumors.

Regulatory T-Cell Responses to Low-Dose Interleukin-2 in HCV-Induced Vasculitis

2011 ◽  
Vol 365 (22) ◽  
pp. 2067-2077 ◽  
Author(s):  
David Saadoun ◽  
Michelle Rosenzwajg ◽  
Florence Joly ◽  
Adrien Six ◽  
Fabrice Carrat ◽  
...  
Keyword(s):  
T Cell ◽  
Regulatory T Cell ◽  
Low Dose ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Cell Responses

scholarly journals Mononucleosis and Antigen-Driven T Cell Responses Have Different Requirements for Interleukin-2 Signaling in Murine Gammaherpesvirus Infection

2010 ◽  
Vol 84 (20) ◽  
pp. 10923-10927 ◽  
Author(s):  
Michael Molloy ◽  
Weijun Zhang ◽  
Edward Usherwood
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
T Cell Response ◽  
Long Term Memory ◽  
Murine Gammaherpesvirus ◽  
Cell Responses ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT Interleukin-2 (IL-2) has been implicated as being necessary for the optimal formation of primary CD8+ T cell responses against various pathogens. Here we have examined the role that IL-2 signaling plays in several aspects of a CD8+ T cell response against murine gammaherpesvirus 68 (MHV-68). Exposure to MHV-68 causes a persistent infection, along with infectious mononucleosis, providing a model for studying these processes in mice. Our study indicates that CD25 is necessary for optimal expansion of the antigen-specific CD8+ T cell response but not for the long-term memory response. Contrastingly, IL-2 signaling through CD25 is absolutely required for CD8+ T cell mononucleosis.

scholarly journals Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial

PLoS Medicine ◽  
2016 ◽  
Vol 13 (10) ◽  
pp. e1002139 ◽  
Author(s):  
John A. Todd ◽  
Marina Evangelou ◽  
Antony J. Cutler ◽  
Marcin L. Pekalski ◽  
Neil M. Walker ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Single Dose ◽  
T Cell ◽  
Regulatory T Cell ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Dose Finding ◽  
Open Label ◽  
Cell Responses

T-Cell Responses to Mitogens in Atomic Bomb Survivors: A Decreased Capacity to Produce Interleukin 2 Characterizes the T Cells of Heavily Irradiated Individuals

2001 ◽  
Vol 155 (1) ◽  
pp. 81-88 ◽  
Author(s):  
Yoichiro Kusunoki ◽  
Tomonori Hayashi ◽  
Yukari Morishita ◽  
Mika Yamaoka ◽  
Mayumi Maki ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Atomic Bomb ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Atomic Bomb Survivors ◽  
Cell Responses

Co-Existing Serological Immune Responses against RHAMM Might Be a Prerequisite for Strong Cellular Immune Responses of CD8-Positive T Cells in RHAMM-R3 Peptide Vaccination for Patients with Different Hematological Malignancies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3671-3671
Author(s):  
Jochen Greiner ◽  
Susanne Hofmann ◽  
Krzysztof Giannopoulos ◽  
Markus Rojewski ◽  
Anna Babiak ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
High Dose ◽  
Clinical Effects ◽  
Peptide Vaccination ◽  
Cell Responses ◽  
Tetramer Staining

Abstract Abstract 3671 Poster Board III-607 For effective elimination of malignant cells by specific T cells a co-activation of CD4- and CD8-positive T cells might be important. We performed two RHAMM-R3 peptide vaccination trials using 300μg and 1000μg for patients with AML, MDS and multiple myeloma overexpressing RHAMM. Similar mild toxicity of both cohorts was found, only mild drug-related adverse events were observed such as erythema and induration of the skin. In the 300μg cohort we detected in 7/10 (70 %) patients specific immune responses and also positive clinical effects in 5/10 (50 %) patients. In the high dose peptide vaccination trial (1000μg peptide) 4/9 (44 %) patients showed positive immune responses. These patients showed an increase of CD8+RHAMM-R3 tetramer+/CD45RA+/CCR7-/CD27-/CD28- effector T cells and an increase of R3-specific CD8+ T cells. In the higher peptide dose cohort three patients showed positive clinical effects. However, higher doses of peptide do not improve the frequency and intensity of immune responses in this clinical trial and might induce immune tolerance. In this work, we investigated the co-existence of serological immune responses against RHAMM detected by a RHAMM-specific ELISA of patients with AML, MDS and multiple myeloma treated in these two peptide vaccination trials. We correlated these results to specific T cell responses of CD8-positive T cells measured by ELISpot assays for interferon gamma and Granzyme B, tetramer staining and chromium release assays. Moreover, these results were compared to the frequency of regulatory T cells. 4/19 patients have a positive serological immune response in ELISA assay, all of these patients developed also strong specific CD8-positive T cell responses during peptide vaccination detected by ELISpot assays and tetramer staining. As expected, peptide vaccination did not result in the induction of humoral immune responses. In further ELISA assays we measured IL-2 and IL-10 levels in the sera of the patients before and three weeks after four vaccinations. While IL-10 levels remained at a rather low level over the time of vaccination, we detected an increase of IL-2 up to the five-fold of the initial levels in four of ten patients. Moreover, we performed a proteome array to detect cytokine and chemokine regulation in sera of patients vaccinated in these two trials during and after RHAMM-R3 peptide vaccination. 36 cytokines, chemokines and acute phase proteins were measured and both cohorts vaccinated with different peptide doses were compared. Taken together, RHAMM-R3 peptide vaccination induced both immunological and clinical responses. Co-existence of immune responses of CD4-positive T cells against the target RHAMM seems to be important for an induction of strong immune responses of CD8-positive T cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Timing of Toll-Like Receptor 9 Agonist Administration in Pneumococcal Vaccination Impacts Both Humoral and Cellular Immune Responses as Well as Nasopharyngeal Colonization in Mice

2012 ◽  
Vol 80 (5) ◽  
pp. 1744-1752 ◽  
Author(s):  
Katrine M. Jensen ◽  
Jesper Melchjorsen ◽  
Frederik Dagnaes-Hansen ◽  
Uffe B. S. Sørensen ◽  
Rune R. Laursen ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Conjugate Vaccine ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Simultaneous Administration ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Content Type ◽  
Cell Responses

ABSTRACTSynthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs, CpG ODN, are Toll-like receptor 9 agonists (TLR9a), which have been used as adjuvants in pneumococcal vaccines to improve antibody responses in immunodeficient patients. Here, we examined whether the coadministration of TLR9a with pneumococcal CRM197-conjugate vaccine enhances protection against pneumococcal colonization, the levels of antipolysaccharide antibodies, and the CD4+T-cell responses. Wild-type BALB/c mice and B-cell-deficient BALB/c Igh-Jtm1Dhumice were immunized twice with the following: (i) PCV alone; (ii) simultaneous PCV and TLR9a; (iii) PCV and then TLR9a, after a 48-h delay; (iv) TLR9a alone; and (v) phosphate-buffered saline. Nasopharyngeal protection, serum antibodies, CD4+T-cell responses, and clearance of bacteremia after intraperitoneal challenge withStreptococcus pneumoniae6B were evaluated. We found decreased nasopharyngeal protection againstS. pneumoniae6B colonization after simultaneous immunization with PCV and TLR9a compared to immunization with PCV alone in wild-type BALB/c mice (P= 0.037). A similar trend was observed in B-cell-deficient BALB/c Igh-Jtm1Dhumice. Simultaneous administration did not enhance antibody levels and lowered the CRM197-specific cytokine release of gamma interferon, interleukin-2 (IL-2), IL-5 and IL-13. Immunization with PCV and then TLR9a, after a 48-h delay, significantly improved nasopharyngeal protection compared to simultaneous administration (P= 0.011). Furthermore, delaying TLR9a delivery increased antibody titers compared to both simultaneous administration (P= 0.001) and PCV immunization alone (P= 0.026). In conclusion, the immunological and clinical impact of adjuvanting a pneumococcal conjugate vaccine (Prevnar; Pfizer) with a TLR9a is highly depended on timing of the adjuvant administration. Thus, careful timing of adjuvant administration may improve novel vaccine formulations.

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