Publications by authors named "Ross B Fulton"

14 Publications

  • Page 1 of 1

Synergy between EphA2-ILs-DTXp, a Novel EphA2-Targeted Nanoliposomal Taxane, and PD-1 Inhibitors in Preclinical Tumor Models.

Mol Cancer Ther 2020 01 9;19(1):270-281. Epub 2019 Oct 9.

Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts.

Combinations of chemotherapy with immunotherapy have seen recent clinical success, including two approvals of anti-PD-1/L1 agents in combination with taxane-based chemotherapy in non-small cell lung cancer and triple-negative breast cancer. Here, we present a study on the combination activity and mechanistic rationale of a novel EphA2-targeted liposomal taxane (EphA2-ILs-DTXp) and anti-PD-1. This combination was highly active in mouse syngeneic tumor models, with complete responses observed in 3 of 5 models. In the EMT-6 tumor model, combination of EphA2-ILs-DTXp with anti-PD-1 resulted in a 60% complete response rate, with durable responses that were resistant to rechallenge. These responses were not observed in the absence of CD8 T cells. Characterization of the immune infiltrates in EMT-6 tumors reveals increased CD8 T cells, increased CD8 IFNγ CTLs, and an increased CD8/regulatory T-cell (Treg) ratio. These immunomodulatory effects were not observed in mice treated with a combination of docetaxel and anti-PD-1. Pharmacokinetic analysis revealed that the AUC of docetaxel was increased 15 times, from 52.1 to 785 ng/mL/hour, when delivered by EphA2-ILs-DTXp. A dose reduction study of EphA2-ILs-DTXp showed a dose-response relationship for both tumor growth inhibition and the CD8/Treg ratio. Our data indicate that synergism between docetaxel and anti-PD-1 is achievable with nanoliposomal delivery.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0414DOI Listing
January 2020

Antibody-mediated targeting of TNFR2 activates CD8 T cells in mice and promotes antitumor immunity.

Sci Transl Med 2019 10;11(512)

Merrimack Pharmaceuticals, Inc., Cambridge, MA 02139, USA.

Tumor necrosis factor receptor 2 (TNFR2) is the alternate receptor for TNF and can mediate both pro- and anti-inflammatory activities of T cells. Although TNFR2 has been linked to enhanced suppressive activity of regulatory T cells (T) in autoimmune diseases, the viability of TNFR2 as a target for cancer immunotherapy has been underappreciated. Here, we show that new murine monoclonal anti-TNFR2 antibodies yield robust antitumor activity and durable protective memory in multiple mouse cancer cell line models. The antibodies mediate potent Fc-dependent T cell costimulation and do not result in significant depletion of T Corresponding human agonistic monoclonal anti-TNFR2 antibodies were identified and also had antitumor effects in humanized mouse models. Anti-TNFR2 antibodies could be developed as a novel treatment option for patients with cancer.
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http://dx.doi.org/10.1126/scitranslmed.aax0720DOI Listing
October 2019

Immune Pharmacodynamic Responses of the Novel Cancer Immunotherapeutic Imprime PGG in Healthy Volunteers.

J Immunol 2019 05 15;202(10):2945-2956. Epub 2019 Apr 15.

Biothera Pharmaceuticals, Inc., Eagan, MN 55121; and.

Imprime PGG (Imprime) is an i.v. administered, yeast β-1,3/1,6 glucan in clinical development with checkpoint inhibitors. Imprime-mediated innate immune activation requires immune complex formation with naturally occurring IgG anti-β glucan Abs (ABA). We administered Imprime to healthy human volunteers to assess the necessity of ABA for Imprime-mediated immunopharmacodynamic (IPD) changes. Imprime (4 mg/kg) was administered i.v. in single and multiple infusions. Subsets of subjects were premedicated with antihistamine and corticosteroid. Peripheral blood was measured before, during and after Imprime administration for IPD changes (e.g., ABA, circulating immune complexes, complement activation, complete blood counts, cytokine/chemokine, and gene expression changes). IPD changes were analyzed based on pretreatment serum ABA levels: low-ABA (<20 μg/ml), mid-ABA (≥20-50 μg/ml), and high-ABA (≥50 μg/ml). At the end of infusion, free serum ABA levels decreased, circulating immune complex levels increased, and complement activation was observed. At ∼1-4 h after end of infusion, increased expression of cytokines/chemokines, a 1.5-4-fold increase in neutrophil and monocyte counts and a broad activation of innate immune genes were observed. Low-ABA subjects typically showed minimal IPD changes except when ABA levels rose above 20 μg/ml after repeated Imprime dosing. Mild-to-moderate infusion-related reactions occurred in subjects with ABA ≥20 μg/ml. Premedications alleviated some of the infusion-related reactions, but also inhibited cytokine responses. In conclusion, ABA levels, being critical for Imprime-mediated immune activation may provide a plausible, mechanism-based biomarker to identify patients most likely to respond to Imprime-based anticancer immunotherapy.
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http://dx.doi.org/10.4049/jimmunol.1801533DOI Listing
May 2019

The Green Prescription Active Families programme in Taranaki, New Zealand 2007-2009: Did it reach children in need?

J Prim Health Care 2015 Sep 1;7(3):192-7. Epub 2015 Sep 1.

Liggins Institute, The University of Auckland, Auckland, and Starship Children's Health, Auckland, New Zealand.

Introduction: The Green Prescription Active Families (GRxAF) programme focuses on overweight/obese children and adolescents, and is family/whanau based. It is an intervention supporting lifestyle changes through weekly sessions (nutrition advice and/or physical activity), and goal setting for the family/whanau for up to 12 months.

Aims: To describe the GRxAF programme in Taranaki and evaluate its reach and engagement, especially for those most at risk of obesity.

Methods: Participant files for each referred child from May 2007 to December 2009 were reviewed. Baseline demographic data, programme graduation information, and weekly activity session attendance were collected.

Results: Of the 109 participants during the audit period, 39% were Maori , 57% New Zealand European (NZE), 3% Pacific, and 1% Other ethnicity. Mean age at entry was 10 (range 4-17) years. Mean duration of programme involvement was five (range 0-12) months. Overall, 33/60 (55%) of the participants completing the programme during the audit period graduated, having made steps towards healthy lifestyle change. In comparison with NZE (68%), a smaller proportion of Maori (40%) graduated (p=0.04). In comparison with those who attended no sessions, participants who attended any sessions were more likely to make positive changes (OR=3.65, 95% CI 1.24-10.8).

Discussion: GRxAF in Taranaki met a need for some obese/overweight children, but not for all families/whanau, especially those over-represented in childhood obesity statistics. Programme delivery for Maori requires improvement, and assessment of readiness to make lifestyle change as an enrolment criteria for all participants is recommended.
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September 2015

The TCR's sensitivity to self peptide-MHC dictates the ability of naive CD8(+) T cells to respond to foreign antigens.

Nat Immunol 2015 Jan 24;16(1):107-17. Epub 2014 Nov 24.

Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.

The strength with which complexes of self peptide and major histocompatibility complex (MHC) proteins are recognized by the T cell antigen receptor (TCR) dictates the homeostasis of naive CD8(+) T cells, but its effect on reactivity to foreign antigens is controversial. As expression of the negative regulator CD5 correlates with self-recognition, we studied CD5(lo) and CD5(hi) naive CD8(+) T cells. Gene-expression characteristics suggested CD5(hi) cells were better poised for reactivity and differentiation than were CD5(lo) cells, and we found that the CD5(hi) pool also exhibited more efficient clonal recruitment and expansion, as well as enhanced reactivity to inflammatory cues, during the recognition of foreign antigen. However, the recognition of complexes of foreign peptide and MHC was similar for both subsets. Thus, CD8(+) T cells with higher self-reactivity dominate the immune response to foreign antigens, with implications for T cell repertoire diversity and autoimmunity.
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http://dx.doi.org/10.1038/ni.3043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270846PMC
January 2015

Aged mice exhibit a severely diminished CD8 T cell response following respiratory syncytial virus infection.

J Virol 2013 Dec 18;87(23):12694-700. Epub 2013 Sep 18.

Department of Microbiology.

Respiratory virus infections in the elderly result in increased rates of hospitalization and death. Respiratory syncytial virus (RSV) is a leading cause of severe virus-induced respiratory disease in individuals over the age of 65. CD8 T cells play a critical role in mediating RSV clearance. While it is clear that T cell immunity declines with age, it is not clear to what extent the CD8 T cell response to RSV is altered. Using aged BALB/c mice, we demonstrated that RSV-specific CD8 T cell responses were significantly reduced in the lungs of aged mice at the peak of the T cell response and that this decrease correlated with delayed viral clearance. Despite a decrease in the overall numbers of RSV-specific CD8 T cells during acute infection, their capacity to produce effector cytokines was not impaired. Following viral clearance, the RSV-specific memory CD8 T cells were similar in total number and phenotype in young and aged mice. Furthermore, following infection with a heterologous pathogen expressing an RSV epitope, RSV-specific memory CD8 T cells exhibited similar activation and ability to provide early control of the infection in young and aged mice. These data demonstrate a decrease in the capacity of aged mice to induce a high-magnitude acute CD8 T cell response, leading to prolonged viral replication, which may contribute to the increased disease severity of RSV infection observed for aged individuals.
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http://dx.doi.org/10.1128/JVI.02282-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3838124PMC
December 2013

Multiple CD4+ T cell subsets produce immunomodulatory IL-10 during respiratory syncytial virus infection.

J Immunol 2011 Sep 15;187(6):3145-54. Epub 2011 Aug 15.

Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242, USA.

The host immune response is believed to contribute to the severity of pulmonary disease induced by acute respiratory syncytial virus (RSV) infection. Because RSV-induced pulmonary disease is associated with immunopathology, we evaluated the role of IL-10 in modulating the RSV-specific immune response. We found that IL-10 protein levels in the lung were increased following acute RSV infection, with maximum production corresponding to the peak of the virus-specific T cell response. The majority of IL-10-producing cells in the lung during acute RSV infection were CD4(+) T cells. The IL-10-producing CD4(+) T cells included Foxp3(+) regulatory T cells, Foxp3(-) CD4(+) T cells that coproduce IFN-γ, and Foxp3(-) CD4(+) T cells that do not coproduce IFN-γ. RSV infection of IL-10-deficient mice resulted in more severe disease, as measured by increased weight loss and airway resistance, as compared with control mice. We also observed an increase in the magnitude of the RSV-induced CD8(+) and CD4(+) T cell response that correlated with increased disease severity in the absence of IL-10 or following IL-10R blockade. Interestingly, IL-10R blockade during acute RSV infection altered CD4(+) T cell subset distribution, resulting in a significant increase in IL-17A-producing CD4(+) T cells and a concomitant decrease in Foxp3(+) regulatory T cells. These results demonstrate that IL-10 plays a critical role in modulating the adaptive immune response to RSV by limiting T-cell-mediated pulmonary inflammation and injury.
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http://dx.doi.org/10.4049/jimmunol.1100764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3304096PMC
September 2011

Not all naïve CD8 T cells are created equal.

Immunol Cell Biol 2011 Jul 12;89(5):576-7. Epub 2011 Apr 12.

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http://dx.doi.org/10.1038/icb.2011.27DOI Listing
July 2011

Foxp3+ CD4 regulatory T cells limit pulmonary immunopathology by modulating the CD8 T cell response during respiratory syncytial virus infection.

J Immunol 2010 Aug 16;185(4):2382-92. Epub 2010 Jul 16.

Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.

Regulatory Foxp3(+) CD4 T cells (Tregs) prevent spontaneous inflammation in the lungs, inhibit allergic and asthmatic responses, and contribute to tolerance to inhaled allergens. Additionally, Tregs have previously been shown to suppress the CD8 T cell response during persistent virus infections. However, little is known concerning the role that Tregs play in modulating the adaptive immune response during acute respiratory virus infections. We show following acute respiratory syncytial virus (RSV) infection that Foxp3(+) CD4 Tregs rapidly accumulate in the lung-draining mediastinal lymph nodes and lungs. BrdU incorporation studies indicate that Tregs undergo proliferation that contributes to their accumulation in the lymph nodes and lungs. Following an acute RSV infection, pulmonary Tregs modulate CD25 expression and acquire an activated phenotype characterized as CD11a(high), CD44(high), CD43(glyco+), ICOS(+), and CTLA-4(+). Surprisingly, in vivo depletion of Tregs prior to RSV infection results in delayed virus clearance concomitant with an early lag in the recruitment of RSV-specific CD8 T cells into the lungs. Additionally, Treg depletion results in exacerbated disease severity, including increased weight loss, morbidity, and enhanced airway restriction. In Treg-depleted mice there is an increase in the frequency of RSV-specific CD8 T cells that coproduce IFN-gamma and TNF-alpha, which may contribute to enhanced disease severity. These results indicate that pulmonary Tregs play a critical role in limiting immunopathology during an acute pulmonary virus infection by influencing the trafficking and effector function of virus-specific CD8 T cells in the lungs and draining lymph nodes.
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http://dx.doi.org/10.4049/jimmunol.1000423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923480PMC
August 2010

T cell epitope specificity and pathogenesis of mouse hepatitis virus-1-induced disease in susceptible and resistant hosts.

J Immunol 2010 Jul 16;185(2):1132-41. Epub 2010 Jun 16.

Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.

Intranasal mouse hepatitis virus-1 (MHV-1) infection of susceptible mouse strains mimics some important pathologic features observed in the lungs of severe acute respiratory syndrome (SARS)-coronavirus-infected humans. The pathogenesis of SARS remains poorly understood, although increasing evidence suggests that immunopathology could play an important role. We previously reported that the adaptive immune response plays an important protective role in MHV-1-infected resistant B6 mice and that both CD4 and CD8 T cells play a significant role in the development of morbidity and lung pathology following intranasal MHV-1 infection of susceptible C3H/HeJ and A/J mice. In this study, we have identified novel CD4 and CD8 epitopes in MHV-1-infected susceptible and resistant strains of mice. Susceptible C3H/HeJ mice mount robust and broad MHV-1-specific CD4 T cell responses, whereas in resistant B6 mice, Ag-specific CD8 T cell responses dominate. We also show that previously immunized susceptible C3H/HeJ mice do not develop any morbidity and are completely protected following a lethal-dose MHV-1 challenge despite mounting only a modest secondary T cell response. Finally, we demonstrate that the resistance displayed by B6 mice is not solely accounted for by the elaboration of a broad and vigorous MHV-1-specific CD8 T cell response, as MHV-1 infection of C3.SW-H2(b)/SnJ mice, which mount an equally robust CD8 T cell response of the same specificity, is still associated with significant morbidity. Thus, identification of novel CD4 and CD8 T cell epitopes for MHV-1 permitted high-resolution analyses of pulmonary T cell responses in a mouse model of SARS.
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http://dx.doi.org/10.4049/jimmunol.0902749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897948PMC
July 2010

Editorial: CD8 T cells cut back on calcium intake in the lungs.

J Leukoc Biol 2010 Jun;87(6):961-4

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http://dx.doi.org/10.1189/jlb.0110035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872533PMC
June 2010

Effects of aging on the adaptive immune response to respiratory virus infections.

Aging health 2009 Dec;5(6):775

Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA, Tel.: +1 319 335 8433.

Severe acute respiratory disease caused by respiratory virus infections in individuals aged 65 years and older and in high-risk adults, such as those with chronic cardiopulmonary disorders, is associated with increased hospitalization and mortality rates. Epidemiological studies have identified influenza virus and respiratory syncytial virus as the most frequent causes of virus-induced respiratory disease in elderly and high-risk adults. Studies in both humans and animal models have established fundamental defects in cell-mediated and humoral immune responses in aged individuals. However, it is not well understood how age specifically alters the immune response to respiratory pathogens. In this review, we will focus our discussion on the major causative agents of severe respiratory virus infections in elderly and high-risk adults and the age-associated defects in the immune response that probably contribute to the increased disease severity observed in these populations.
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http://dx.doi.org/10.2217/ahe.09.69DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2822389PMC
December 2009

A proteomics approach to cloning fenestrin from the nuclear exchange junction of tetrahymena.

J Eukaryot Microbiol 2008 Jul-Aug;55(4):245-56

Biology Department, St. Olaf College, Northfield, Minnesota 55057, USA.

We set out to find the "fenestrin" gene, a gene whose protein is associated with numerous cellular apertures, including the nuclear exchange junction in mating Tetrahymena thermophila. First we developed protocols for imaging and isolating intact nuclear exchange junctions from conjugating cells. Proteins from these junctions were purified using SDS-PAGE, subjected to limited proteolysis, and precise molecular weights were determined by mass spectrometry. Using Protein Prospector software and the published Tetrahymena Genome Database, genes for 15 of the most abundant proteins found in our extracts were identified. The most promising candidate was cloned by PCR, fused to yellow fluorescent protein (YFP), and placed under the control of an inducible metallothionein promoter. YFP-localization within live Tetrahymena transformants strongly suggested that one of these genes encoded the fenestrin protein, a result that was subsequently confirmed by Western blotting.
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http://dx.doi.org/10.1111/j.1550-7408.2008.00337.xDOI Listing
January 2009

Regulation of cytokine production by virus-specific CD8 T cells in the lungs.

J Virol 2008 Aug 4;82(16):7799-811. Epub 2008 Jun 4.

Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.

Inflammation and the elimination of infected host cells during an immune response often cause local tissue injury and immunopathology, which can disrupt the normal functions of tissues such as the lung. Here, we show that both virus-induced inflammation and the host tissue environment combine to influence the capacity of virus-specific CD4 and CD8 T cells to produce cytokines in various tissues. Decreased production of cytokines, such as IFN-gamma and TNF-alpha, by antigen-specific T cells is more pronounced in peripheral tissues, such as the lung and kidney, than in secondary lymphoid organs, such as the spleen or lymph nodes. We also demonstrate that tissues regulate cytokine production by memory T cells independently of virus infection, as memory T cells that traffic into the lungs of naïve animals exhibit a reduced ability to produce cytokines following direct ex vivo peptide stimulation. Furthermore, we show that cytokine production by antigen-specific memory CD4 and CD8 T cells isolated from the lung parenchyma can be rescued by stimulation with exogenous peptide-pulsed antigen-presenting cells. Our results suggest that the regulation of T-cell cytokine production by peripheral tissues may serve as an important mechanism to prevent immunopathology and preserve normal tissue function.
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http://dx.doi.org/10.1128/JVI.00840-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2519597PMC
August 2008