Browsing by Subject "immunotherapy"

Now showing 1 - 5 of 5
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    Anti-CAR antibody response in SIV infected rhesus macaques
    (2022-11-28) Davey, Brianna, C; Pampusch, Mary, S; Cartwright, Emily, K; Abdelaal, Hadia, M; Rakasz, Eva, G; Rendahl, Aaron; Berger, Edward, A; Skinner, Pamela, J; skinn002@umn.edu; Skinner, Pamela, J; Skinner laboratory
    T cells expressing a simian immunodeficiency (SIV)-specific chimeric antigen receptor (CAR) and the follicular homing molecule, CXCR5, were infused into antiretroviral therapy (ART) suppressed, SIV-infected rhesus macaques to assess their ability to localize to the lymphoid follicle and control the virus upon ART interruption. The cells did not persist in the animals beyond 28 days. Development of anti-CAR antibodies could be responsible for the lack of persistence. Potential antigenic sites on the anti-SIV CAR used in these studies included domains 1 and 2 of CD4, the carbohydrate recognition domain (CRD) of mannose-binding lectin (MBL), and an extracellular domain of the costimulatory molecule, CD28, along with short linker sequences. Using a flow cytometry based assay and target cells expressing the CAR/CXCR5 construct, we examined the serum of the CAR T-cell treated animals to determine that the animals had developed an anti-CAR antibody response after infusion. Binding sites for the anti-CAR antibodies were identified by using alternative CARs transduced into target cells and by preincubation of the target cells with a CD4 blocking antibody. All of the treated animals developed antibodies in their serum that bound to CAR-T cells and the majority were capable of inducing an ADCC response. The CD4 antibody-blocking assay suggests that the dominant immunogenic components of this CAR are the CD4 domains with a possible additional site of the CD28 domain with its linker.
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    Contributions Of Signal Transducer And Activator Of Transcription 3 To Tumor And Immune Cell Functions In Breast Cancer
    (2016-10) Chuntova, Polly
    The studies presented in this thesis demonstrate a novel link between activation of the FGFR pathway, alterations of the tumor microenvironment and tumor immune response in mammary tumorigenesis. These studies are the first to demonstrate that FGFR signaling in epithelial cells leads to accumulation of the ECM component hyaluronan (HA) through increased production of pro-inflammatory cytokines and activation of the STAT3 pathway. Therapeutic inhibition of STAT3 in vivo reduced HA accumulation, which correlated with reduced tumor burden. Nonetheless, STAT3 inhibition did not result in tumor regression, suggesting that additional pro-tumorigenic mechanisms are able to sustain tumor growth. Previous work has shown that FGFR1 activation leads to rapid recruitment of macrophages with pro-tumorigenic functions. We hypothesized that as TAMs differentiate in the presence of FGFR1-driven IL-6 family of cytokines, the STAT3 signaling pathway would be activated and would influence TAM differentiation. Therefore, further studies focused on delineating the STAT3-dependent phenotype and function of mammary TAMs. Utilizing a mouse model of genetic STAT3 ablation within myeloid cells demonstrated decreased tumor latency and increased tumor growth rate in conditional-STAT3∆/∆ mice compared to control animals. These results provide evidence to the hypothesis that STAT3 activation in different tumor and immune cell populations can result in both pro- and anti-tumor phenotypes, and detailed understanding of these mechanisms is necessary for developing effective therapeutic approaches.
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    Effect of anti-amyloid β antibody on Aβ trafficking at the blood-brain barrier
    (2021-12) Li, Chenxu
    Alzheimer’s disease (AD) is broadly recognized as a global public health priority, which has been characterized by the atrophy of the brain and the impairment of memory. The abnormal accumulation of amyloid-beta (Aβ) peptides in the brain have been identified as a major contributor to AD. Thus, the use of monoclonal antibodies (mAbs) to alter Aβ trafficking kinetics at the blood-brain barrier (BBB) represents a promising therapeutic strategy. While anti-Aβ antibodies have been shown to bind and clear Aβ deposits from the brain, the effects of anti-Aβ antibodies on Aβ trafficking in the blood-to-brain direction remain unclear. Plasma Aβ levels are shown to correlate with AD risk, and the overall amount of Aβ in the periphery is estimated to be ~10 fold greater than the amount in the brain. Therefore, Aβ trafficking in the blood-to-brain direction cannot be ignored. We proposed that anti-Aβ mAbs are not required to enter the brain to elicit their therapeutic actions, and mAbs in the circulatory system would be sufficiently effective to change the Aβ trafficking at the BBB. To clarify the effects of anti-Aβ antibodies on Aβ trafficking in both the blood-to-brain and brain-to-blood directions, we conducted a series of Aβ uptake/ transport assays with BBB cell monolayers following exposure to IgG4.1, a well-characterized anti-Aβ mAb. In a wild-type mice model, brain uptake of 125I labeled Aβ40 tended to increase in the presence of systemically injected IgG4.1. In studies examining the endothelial cell uptake of Aβ in vitro, IgG4.1 significantly prevented both Aβ40 and Aβ42 cellular uptake through the formation of immune complexes. Moreover, Aβ42 has a higher magnitude of cellular uptake and is more susceptible to IgG4.1 than that of Aβ40. Overall, our in vitro studies support the premise that IgG4.1 affects Aβ trafficking kinetics (especially Aβ42) without entering into the brain.
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    Targeted Biological and Cellular Immunotherapies for Osteosarcoma
    (2023-12) Robbins, Gabrielle
    Osteosarcoma (OSA) is the most common cancer of the bone and third most common cancer diagnosed in children and adolescent. The five-year survival rate for OSA patients approaches 70%; however, this rate drops to less than 30% with metastatic disease. There have been no changes in treatment options or patient outcome in over four decades. Consequently, there is a pressing need to identify actionable targets and develop novel immunotherapies for the treatment of OSA. Immunotherapies have proven to be successful for the treatment of hematological malignancies as well as some solid tumors, including cancers of the lung, kidney, and bladder. To date, OSA remains impervious to treatment with immunotherapies. We hypothesize that treating OSA using targeted immunotherapies will decrease proliferation in vitro and decrease tumor growth and invasion/migration while improving survival in vivo. To this end, we evaluated the efficacy of two different, targeted immunotherapies for the treatment of OSA. First, we tested a monoclonal antibody (mAb) targeting SEMA4D, a candidate gene previously identified in a forward genetic screen of OSA. Anti-SEMA4D treatment decreased OSA cell proliferation and MET production in vitro. In vivo, we saw anti-SEMA4D treatment slow tumor growth, decrease collagen deposition, decrease the incidence of metastasis, and modulate the immune cell infiltrate. OSA is traditionally an immunologically ‘cold’ tumor with poor immune cell infiltration and activity. As such, we also utilized a cell-based approach to target OSA using natural killer (NK) cells. NK cells are lymphocytes of the innate immune system involved in killing infected or malignantly transformed cells. Previous work has shown that unmanipulated NK cells are minimally effective in the treatment of cancer, likely due to poor persistence and suppression within the tumor microenvironment. To circumvent these challenges, we delivered a CD70-specific chimeric antigen receptor (CAR), soluble interleukin 15 (IL-15), and a transforming growth factor beta (TGF-β) dominant negative mutant receptor. These armored CD70-CAR NK cells show remarkable in vitro killing and pro-inflammatory cytokine activity against OSA. In vivo, we see armored CD70-NK cells home to the tumor as well as sustained persistence and strong anti-tumor activity. The goal of this work was to develop novel and effective therapies to treat OSA for use in the clinical setting. Future work will focus on developing multi-targeted approaches for these hard to treat and genetically diverse tumors.
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    Transcriptomic data from RNA Sequencing of canine high grade glioma tumor samples
    (2024-11-15) Arnold, Susan A; Pluhar, G. Elizabeth; Abrahante Llorens, Juan E; saarnold@umn.edu; Arnold, Susan; University of Minnesota Canine Brain Tumor Program
    These files contain the raw data for bulk RNA sequencing performed on canine high grade glioma tumor samples. These samples were obtained from three breeds of dogs: French bulldogs, boxers, and Boston terriers. All dogs were enrolled in immunotherapy clinical trials within the University of Minnesota Canine Brain Tumor Program. They were obtained from two different time points relative to treatment: pre-treatment and post-treatment. Treatment consisted of surgical resection and immunotherapy. The purpose of these data are to provide a comprehensive profile of how canine high grade glioma transcriptomes change in response to immunotherapy treatment, and to determine if there are breed-associated changes in differential gene expression.