Biology subjects

Carback, R. T.

Publications and source records attributed to Carback, R. T..

4 recordsLinked to original sources

bioRxiv2022

T-cell targeted immunotherapy against the tumor associated antigen survivin (BIRC5) as a potential neoadjuvant immunotherapy for triple negative breast cancer.

A triple negative breast cancer (TNBC) model using the murine 4T1 tumor cell line was used to explore the efficacy of an adjuvanted survivin (SVN)-peptide microparticle vaccine using tumor growth as the outcome metric. We first performed tumor cell dose titration studies to determine a tumor cell dose that resulted in sufficient tumor takes but minimal morbidity/mortality within the required study period. Later, in a second cohort of mice, the SVN-peptide microparticle vaccine was administered via intraperitoneal injection at study start with a second dose given 14 days later. An orthotopic injection of 4T1 cells into the mammary tissue was performed on the same day as the administration of the second vaccine dose. The mice were followed for up to 41 days with subcutaneous measurements of tumor volume made every 3-4 days. Vaccination with SVN peptides was associated with a peptide antigen-specific {gamma}IFN Elispot response in the murine splenocyte population but was absent from the control microparticle group. At end of study, we found that vaccination with adjuvanted SVN-peptide microparticles resulted in statistically significant slower primary tumor growth rates in BALB/c mice challenged with 4T1 cells relative to the control peptide-less vaccination group. These studies suggest that T-cell immunotherapy specifically targeting survivin might be an applicable neoadjuvant immunotherapy therapy for TNBC. More pre-clinical studies and clinical trials will be needed to explore this concept further.

immunology↗

bioRxiv2020

Paired SARS CoV-2 Spike Protein Mutations Observed During Ongoing SARS-CoV-2 Viral Transfer from Humans to Minks and Back to Humans

A mutation analysis of SARS-CoV-2 genomes collected around the world sorted by sequence, date, geographic location, and species has revealed a large number of variants from the initial reference sequence in Wuhan. This analysis also reveals that humans infected with SARS-CoV-2 have infected mink populations in the Netherlands, Denmark, United States, and Canada. In these animals, a small set of mutations in the spike protein receptor binding domain (RBD), often occurring in specific combinations, has transferred back into humans. The viral genomic mutations in minks observed in the Netherlands and Denmark show the potential for new mutations on the SARS-CoV-2 spike protein RBD to be introduced into humans by zoonotic transfer. Our data suggests that close attention to viral transfer from humans to farm animals and pets will be required to prevent build-up of a viral reservoir for potential future zoonotic transfer.

genetics↗

bioRxiv2020

anti-IL-6 versus anti-IL-6R Blocking Antibodies to Treat Acute Ebola Infection in BALB/c Mice with Potential Implications for Treating Patients Presenting with COVID-19

Cytokine release syndrome (CRS) is known to be a factor in morbidity and mortality associated with acute viral infections including those caused by filoviruses and coronaviruses. IL-6 has been implicated as a cytokine negatively associated with survival after filovirus and coronavirus infection. However, IL-6 has also been shown to be an important mediator of innate immunity and important for the host response to an acute viral infection. Clinical studies are now being conducted by various researchers to evaluate the possible role of IL-6 blockers to improve outcomes in critically ill patients with CRS. Most of these studies involve the use of anti-IL-6R monoclonal antibodies (-IL-6R mAbs). We present data showing that direct neutralization of IL-6 with an -IL-6 mAb in a BALB/c Ebolavirus (EBOV) challenge model produced a statistically significant improvement in outcome compared with controls when administered within the first 24 hours of challenge and repeated every 72 hours. A similar effect was seen in mice treated with the same dose of -IL-6R mAb when the treatment was delayed 48 hrs post-challenge. These data suggest that direct neutralization of IL-6, early during the course of infection, may provide additional clinical benefits to IL-6 receptor blockade alone during treatment of patients with virus-induced CRS.

immunology↗

bioRxiv2020

An Effective CTL Peptide Vaccine for Ebola Zaire Based on Survivors' CD8+ Targeting of a Particular Nucleocapsid Protein Epitope with Potential Implications for COVID-19 Vaccine Design

The 2013-2016 West Africa EBOV epidemic was the biggest EBOV outbreak to date. An analysis of virus-specific CD8+ T-cell immunity in 30 survivors showed that 26 of those individuals had a CD8+ response to at least one EBOV protein. The dominant response (25/26 subjects) was specific to the EBOV nucleocapsid protein (NP). It has been suggested that epitopes on the EBOV NP could form an important part of an effective T-cell vaccine for Ebola Zaire. We show that a 9-amino-acid peptide NP44-52 (YQVNNLEEI) located in a conserved region of EBOV NP provides protection against morbidity and mortality after mouse adapted EBOV challenge. A single vaccination in a C57BL/6 mouse using an adjuvanted microsphere peptide vaccine formulation containing NP44-52 is enough to confer immunity in mice. Our work suggests that a peptide vaccine based on CD8+ T-cell immunity in EBOV survivors is conceptually sound and feasible. Nucleocapsid proteins within SARS-CoV-2 contain multiple class I epitopes with predicted HLA restrictions consistent with broad population coverage. A similar approach to a CTL vaccine design may be possible for that virus.

immunology↗