Abstract 616: The novel α-Gal-based immunotherapy AGI-134 invokes CD8+ T cell-mediated immunity by driving tumor cell destruction, phagocytosis and tumor-associated antigen cross-presentation via multiple antibody-mediated effector functions

Author(s):  
Jenny L. Middleton ◽  
Oliver Schulz ◽  
Amber Charlemagne ◽  
Sascha A. Kristian ◽  
Stephen Michael Shaw
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ryan D. Pardy ◽  
Stefanie F. Valbon ◽  
Brendan Cordeiro ◽  
Connie M. Krawczyk ◽  
Martin J. Richer

AbstractZika virus (ZIKV) has emerged as an important global health threat, with the recently acquired capacity to cause severe neurological symptoms and to persist within host tissues. We previously demonstrated that an early Asian lineage ZIKV isolate induces a highly activated CD8 T cell response specific for an immunodominant epitope in the ZIKV envelope protein in wild-type mice. Here we show that a contemporary ZIKV isolate from the Brazilian outbreak severely limits CD8 T cell immunity in mice and blocks generation of the immunodominant CD8 T cell response. This is associated with a more sustained infection that is cleared between 7- and 14-days post-infection. Mechanistically, we demonstrate that infection with the Brazilian ZIKV isolate reduces the cross-presentation capacity of dendritic cells and fails to fully activate the immunoproteasome. Thus, our study provides an isolate-specific mechanism of host immune evasion by one Brazilian ZIKV isolate, which differs from the early Asian lineage isolate and provides potential insight into viral persistence associated with recent ZIKV outbreaks.


Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 606
Author(s):  
Giuseppe Cappellano ◽  
Hugo Abreu ◽  
Chiara Casale ◽  
Umberto Dianzani ◽  
Annalisa Chiocchetti

The first vaccines ever made were based on live-attenuated or inactivated pathogens, either whole cells or fragments. Although these vaccines required the co-administration of antigens with adjuvants to induce a strong humoral response, they could only elicit a poor CD8+ T-cell response. In contrast, next-generation nano/microparticle-based vaccines offer several advantages over traditional ones because they can induce a more potent CD8+ T-cell response and, at the same time, are ideal carriers for proteins, adjuvants, and nucleic acids. The fact that these nanocarriers can be loaded with molecules able to modulate the immune response by inducing different effector functions and regulatory activities makes them ideal tools for inverse vaccination, whose goal is to shut down the immune response in autoimmune diseases. Poly (lactic-co-glycolic acid) (PLGA) and liposomes are biocompatible materials approved by the Food and Drug Administration (FDA) for clinical use and are, therefore, suitable for nanoparticle-based vaccines. Recently, another candidate platform for innovative vaccines based on extracellular vesicles (EVs) has been shown to efficiently co-deliver antigens and adjuvants. This review will discuss the potential use of PLGA-NPs, liposomes, and EVs as carriers of peptides, adjuvants, mRNA, and DNA for the development of next-generation vaccines against endemic and emerging viruses in light of the recent COVID-19 pandemic.


2005 ◽  
Vol 35 (10) ◽  
pp. 2970-2981 ◽  
Author(s):  
Andreas Limmer ◽  
Jutta Ohl ◽  
Gerhard Wingender ◽  
Martina Berg ◽  
Frank Jüngerkes ◽  
...  

2018 ◽  
pp. canres.3297.2017 ◽  
Author(s):  
Lisanne Heim ◽  
Juliane Friedrich ◽  
Marina Engelhardt ◽  
Denis I Trufa ◽  
Carol I. Geppert ◽  
...  

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2591-2591
Author(s):  
Tanguy Y. Seiwert ◽  
Colette Shen ◽  
Jessica M. Frakes ◽  
Jiaxin Niu ◽  
Jared Weiss ◽  
...  

2591 Background: Despite recent advances, resistance to immune checkpoint inhibitors (ICI), observed in over 80% of treated patients, is currently the main challenge in immuno-oncology. Intense efforts are being made to identify combination therapies that could improve ICI response rates. NBTXR3, a novel radioenhancer administered by direct intratumoral injection (ITI), is designed at the nanoscale to increase radiation therapy (XRT) dose deposit within tumor cells and subsequent tumor cell killing, without increasing toxicity to surrounding healthy tissue. Here we present evidence that NBTXR3 activated by XRT primes the immune system, producing an anti-tumor response, including activation of the cGAS-STING pathway, that overcomes anti-PD-1 resistance both in mice models and patients. Methods: Abscopal assays were conducted in immunocompetent mice. Anti-PD-1 sensitive or resistant tumor cell lines, were injected in both flanks of mice. Intratumoral injection of NBTXR3 (or vehicle) followed by XRT was performed in right flank (primary) tumors only. Some mice also received anti-PD-1 injections. Tumor growth was monitored, and tumor immune cell infiltrates analyzed by immunohistochemistry (IHC). Separately, in the phase II/III randomized Act.in.Sarc [NCT02379845] trial patients with locally advanced soft tissue sarcoma (STS) received either NBTXR3+XRT or XRT alone followed by tumor resection. Pre- and post-treatment tumor samples from patients in both groups were analyzed by IHC and Digital Pathology for immune biomarkers. The safety and efficacy (RECIST 1.1/iRECIST) of NBTXR3 plus stereotactic body radiotherapy (SBRT) in combination with anti-PD-1 is being evaluated in three cohorts of patients with advanced cancers [NCT03589339]. Results: Pre-clinical studies demonstrated that NBTXR3+XRT induces an immune response not observed with XRT alone and enhances systemic control. IHC showed significant increase of CD8+ T-cell infiltrates in both NBTXR3+XRT treated and untreated tumors compared to XRT alone. Similarly, increased CD8+ T-cell and decreased FOXP3+ Treg density (pre- vs post-treatment) was observed in tumor tissues from STS patients treated with NBTXR3+XRT. Furthermore, NBTXR3+XRT in combination with anti-PD-1 improved local and systemic control in mice bearing anti-PD-1 resistant lung tumors, as well as reduced the number of spontaneous lung metastases. Preliminary efficacy data from the first in human trial of NBTXR3+XRT in combination with anti-PD-1 showed tumor regression in the majority of patients (8/9). Of note, tumor regression was observed in 6/7 pts who had progressed on prior anti-PD-1. Conclusions: The clinical efficacy of NBTXR3+XRT has been demonstrated as a single agent. We now demonstrate that it potentiates anti-PD-1 treatment to overcome resistance mechanisms. These results highlight the potential of NBTXR3+XRT to positively impact the immuno-oncology field. Clinical trial information: NCT03589339.


Blood ◽  
2013 ◽  
Vol 122 (1) ◽  
pp. 55-60 ◽  
Author(s):  
Monique L. Ong ◽  
Matthew E. Wikstrom ◽  
Peter Fleming ◽  
Marie J. Estcourt ◽  
Paul J. Hertzog ◽  
...  

Key Points Fully functional CD8 T-cell responses, control of infection, and protection from organ pathology are attained without cross-presentation. Direct presentation generates responses that limit disease and ensure host survival despite the presence of immunomodulatory viral proteins.


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