Eradication of murine bladder carcinoma by intratumor injection of a bicistronic adenoviral vector carrying cDNAs for the IL-12 heterodimer and its inhibition by the IL-12 p40 subunit homodimer.

Chen, L; Chen, D; Block, Edward R.; O’Donnell, Michael A.; Küfe, Donald; Clinton, Steven K.

doi:10.4049/jimmunol.159.1.351

Cited by 127 publications

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“…These adjuvants potentiate the Th1 immune response, ensuring robust anti-viral immunity. Consistently, IL-12 has been shown to enhance clinical benefit by promoting Th1 response in cancer patients (22,(26)(27)(28). Similarly, GM-CSF has been shown to improve immune response primarily by potentiating dendritic cells (29,30).…”

Section: Introductionmentioning

confidence: 90%

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Immunogenicity and protective efficacy of an influenza virus-like particle-based SARS-CoV-2 hybrid vaccine candidate in rhesus macaques

Rahman,

Bommireddy,

Routhu

et al. 2024

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus co-infections present a heightened COVID-19 disease and hospitalization cases. Here, we studied the immunogenicity and efficacy of an influenza-A/PR8 virus-like particle (FluVLP)-based hybrid vaccine candidate displaying GPI-anchored SARS-CoV-2 receptor binding domain fused to GM-CSF and GPI-anchored interleukin-12 (FluVLP-RBD) in rhesus macaques. Animals (n=4/group) received two doses of either FluVLP or FluVLP-RBD vaccine four weeks apart and were challenged with SARS-CoV-2 (WA1/2020) infection via intranasal and intratracheal routes. We determined vaccine-induced IgG and neutralizing antibody titers in serum and their association with viral replication in the lower and upper airways (lung, throat, and nose) and lung-associated pathologies. FluVLP-RBD vaccine induced a strong binding IgG in serum against multiple SARS-CoV-2 variants (WA1/2020, Delta and Omicron; BA.1). Both vaccines induced strong influenza A/PR8-specific IgG. Following the SARS-CoV-2 challenge, all four animals in the FluVLP-RBD group showed a profound control of virus replication in all three airway compartments as early as day 2 through day 10 (day of euthanasia). This level of viral control was not observed in the FluVLP group as 2-3 animals exhibited high virus replication in all three airway compartments. The protection in the FluVLP-RBD vaccinated group correlated positively with post challenge neutralizing antibody titer. These results demonstrated that a FluVLP-based hybrid SARS-CoV-2 vaccine induces strong antibody responses against influenza-A/PR8 and multiple SARS-CoV-2 RBD variants and protects from SARS-CoV-2 replication in multiple compartments in macaques. These findings provide important insights for developing multivalent vaccine strategies for respiratory viruses.

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Section: Introductionmentioning

confidence: 90%

“…The copyright holder for this preprint (which this version posted May 24, 2024. ; https://doi.org/10.1101/2024.05. 24.595657 doi: bioRxiv preprint promoting Th1 response in cancer patients (22,(26)(27)(28). Similarly, GM-CSF has been shown to improve immune response primarily by potentiating dendritic cells (29,30).…”

Section: Introductionmentioning

confidence: 99%

Immunogenicity and protective efficacy of an influenza virus-like particle-based SARS-CoV-2 hybrid vaccine candidate in rhesus macaques

Rahman,

Bommireddy,

Routhu

et al. 2024

Preprint

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Role of NK and T cells in IL-12-induced anti-tumor response against hepatic colon carcinoma

et al. 1999

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IL‐12 is an immuno‐regulatory cytokine that has been shown to generate a potent NK and Th1 response in a variety of laboratory models. However, the detailed immune development in the hepatic tumor model by IL‐12‐mediated gene therapy has not been clarified. In our previous study, intra‐tumoral transfer of Adv.mIL‐12 (5 × 108 pfu) to the MCA26 colon carcinoma liver tumor induced an effective anti‐tumor response, extending the median survival time from 29 to over 54 days, while 25% of the animals became tumor‐free after a single treatment. In this work, we show that NK cells are responsible for the early, and both NK and T cells for the long‐term, Adv.mIL‐12‐induced immune response. Immuno‐histopathological analysis of the tumor and in vitro cytotoxicity study of the mononuclear cells of the liver show that NK cells are the first to infiltrate and mediate tumor cell killing, as early as 48 hr after Adv.mIL‐12 treatment. In vivo and in vitro depletion of these cells completely abolishes this early anti‐tumor response. This activity can be observed in both populations of conventional NK and NKT cells in vitro and in athymic nude mice in vivo. However, the early NK response alone is not sufficient. In vivo T‐cell depletion in both the primary tumor treatment and the long‐term survival re‐challenge study reveals that T cells in addition to NK cells are required in the development of the long‐term survival and immunity attributed to Adv.mIL‐12 gene therapy in this orthotopic tumor model of colon carcinoma. Int. J. Cancer81:813–819, 1999. © 1999 Wiley‐Liss, Inc.

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Characterization of mouse interleukin-12 p40 homodimer binding to the interleukin-12 receptor subunits

et al. 1999

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Interleukin-12 (IL-12) is a heterodimeric cytokine composed of two disulfide-bonded sub-units, p35 and p40, which has important regulatory effects on T cells and natural killer (NK) cells. In contrast to heterodimeric IL-12, a homodimer of the p40 subunit, designated (p40) 2 , has been shown to be a potent IL-12 antagonist. To study the interaction between (p40) 2 and the known IL-12 receptor (IL-12R) subunits, IL-12R g 1 and IL-12R g 2, we directly measured the binding activity of mouse (p40) 2 to ConA-activated lymphoblasts and purified B cells from splenocytes of C57BL/6J mice. These results demonstrated the presence of both high (K d about 5 pM) and low affinity (K d about 15 nM) binding sites for mouse 125 I-labeled (p40) 2. To elucidate which of the IL-12R subunits binds mouse (p40) 2 , binding studies of mouse 125 I-labeled (p40) 2 to Ba/F3 cells expressing recombinant mouse IL-12R g 1 and/or mouse IL-12R g 2 were carried out. Mouse IL-12R g 1 bound mouse 125 I-labeled (p40) 2 with high and low affinities, comparable to that observed on Con A blasts and B cells. In contrast, mouse IL-12R g 2 bound mouse 125 I-labeled (p40) 2 very poorly. These data demonstrate that similar to IL-12, mouse (p40) 2 binds with both high and low affinity to Con A blasts and B cells, and that IL-12R g 1 is responsible for mediating the specific binding of mouse (p40) 2 .

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Eradication of murine bladder carcinoma by intratumor injection of a bicistronic adenoviral vector carrying cDNAs for the IL-12 heterodimer and its inhibition by the IL-12 p40 subunit homodimer.

Cited by 127 publications

References 0 publications

Immunogenicity and protective efficacy of an influenza virus-like particle-based SARS-CoV-2 hybrid vaccine candidate in rhesus macaques

Immunogenicity and protective efficacy of an influenza virus-like particle-based SARS-CoV-2 hybrid vaccine candidate in rhesus macaques

Role of NK and T cells in IL-12-induced anti-tumor response against hepatic colon carcinoma

Characterization of mouse interleukin-12 p40 homodimer binding to the interleukin-12 receptor subunits

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