Browsing by Subject "Immune response"

Now showing 1 - 10 of 22
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    17-Beta estradiol-induced modulation of the immune system
    (1984) Myers, Michael Joseph
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    A Bayesian phase I/II biomarker-based design for identifying subgroup-specific optimal dose for immunotherapy
    (Sage, 2022) Guo, Beibei; Zang, Yong; Biostatistics and Health Data Science, School of Medicine
    Immunotherapy is an innovative treatment that enlists the patient’s immune system to battle tumors. The optimal dose for treating patients with an immunotherapeutic agent may differ according to their biomarker status. In this article, we propose a biomarker-based phase I/II dose-finding design for identifying subgroup-specific optimal dose for immunotherapy (BSOI) that jointly models the immune response, toxicity, and efficacy outcomes. We propose parsimonious yet flexible models to borrow information across different types of outcomes and subgroups. We quantify the desirability of the dose using a utility function and adopt a two-stage dose-finding algorithm to find the optimal dose for each subgroup. Simulation studies show that the BSOI design has desirable operating characteristics in selecting the subgroup-specific optimal doses and allocating patients to those optimal doses, and outperforms conventional designs.
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    Adeno-Associated Virus D-Sequence-Mediated Suppression of Expression of a Human Major Histocompatibility Class II Gene: Implications in the Development of Adeno-Associated Virus Vectors for Modulating Humoral Immune Response
    (Mary Ann Liebert, Inc., 2020-05) Kwon, Hyung-Joo; Qing, Keyun; Ponnazhagan, Selvarangan; Wang, Xu-Shan; Markusic, David M.; Gupte, Siddhant; Boye, Shannon E.; Srivastava, Arun; Pediatrics, School of Medicine
    A 20-nt long sequence, termed the D-sequence, in the adeno-associated virus (AAV) inverted terminal repeat was observed to share a partial sequence homology with the X-box in the regulatory region of the human leukocyte antigen DRA (HLA-DRA) promoter of the human major histocompatibility complex class II (MHC-II) genes. The D-sequence was also shown to specifically interact with the regulatory factor binding to the X-box (RFX), binding of which to the X-box is a critical step in the MHC-II gene expression, suggesting that D-sequence might compete for RFX transcription factor binding, thereby suppressing expression from the MHC-II promoter. In DNA-mediated transfection experiments, using a reporter gene under the control of the HLA-DRA promoter, D-sequence oligonucleotides were found to inhibit expression of the reporter gene expression in HeLa and 293 cells by ∼93% and 96%, respectively. No inhibition was observed when nonspecific synthetic oligonucleotides were used. D-sequence oligonucleotides had no effect on expression from the cytomegalovirus immediate-early gene promoter. Interferon-γ-mediated activation of MHC-II gene expression was also inhibited by D-sequence oligonucleotides as well as after infection with either the wild-type AAV or transduction with recombinant AAV vectors. These studies suggest that the D-sequence-mediated downregulation of the MHC-II gene expression may be exploited toward the development of novel AAV vectors capable of dampening the host humoral response, which has important implication in the optimal use of these vectors in human gene therapy.
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    BIPSE: A Biomarker-based Phase I/II Design for Immunotherapy Trials with Progression-free Survival Endpoint
    (Wiley, 2022) Guo, Beibei; Zang, Yong; Biostatistics and Health Data Science, School of Medicine
    A Bayesian biomarker-based phase I/II design (BIPSE) is presented for immunotherapy trials with a progression-free survival (PFS) endpoint. The objective is to identify the subgroup-specific optimal dose, defined as the dose with the best risk-benefit tradeoff in each biomarker subgroup. We jointly model the immune response, toxicity outcome, and PFS with information borrowing across subgroups. A plateau model is used to describe the marginal distribution of the immune response. Conditional on the immune response, we model toxicity using probit regression and model PFS using the mixture cure rate model. During the trial, based on the accumulating data, we continuously update model estimates and adaptively randomize patients to doses with high desirability within each subgroup. Simulation studies show that the BIPSE design has desirable operating characteristics in selecting the subgroup-specific optimal doses and allocating patients to those optimal doses, and outperforms conventional designs.
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    Birch pollen allergen-induced dsDNA release activates cGAS-STING signaling and type 2 immune response in mice
    (Elsevier, 2025-03-31) Chenuet, Pauline; Mellier, Manon; Messaoud-Nacer, Yasmine; Culerier, Elodie; Marquant, Quentin; Fauconnier, Louis; Rouxel, Nathalie; Ledru, Aurélie; Rose, Stéphanie; Ryffel, Bernhard; Apetoh, Lionel; Quesniaux, Valérie F. J.; Togbe, Dieudonnée; Medicine, School of Medicine
    Detecting cytoplasmic or extracellular DNA from host or pathogen origin by DNA sensor cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) triggers immune responses with secretion of type I interferons and inflammatory cytokines. However, STING agonists function as type-2 adjuvant promoting allergic asthma. Here, we asked how cGAS/STING signaling pathway influences allergen-induced type-2 immune responses in models of allergic airway diseases induced by birch pollen extract, house dust mite, or ovalbumin plus Alum. We report increased extracellular dsDNA in the airways, together with cGAS and STING gene expression, following allergen challenge in these models, correlating dsDNA and type-2 cytokine IL-4, IL-5, and IL-13 release. Allergen-induced type-2 immune responses were reduced in cGAS- or STING-deficient mice. Further, blocking cGAS function with the specific inhibitor RU.521 protected mice from birch pollen allergen-induced airway inflammation and type-2 immune responses. Thus, DNA sensing by cGAS contributes to type-2 immune responses and may represent a therapeutic target for allergic lung inflammation.
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    Clinical lung xenotransplantation – what donor genetic modifications may be necessary?
    (Wiley, 2012) Cooper, David K. C.; Ekser, Burcin; Burlak, Christopher; Ezzelarab, Mohamed; Hara, Hidetaka; Paris, Leela; Tector, A. Joseph; Phelps, Carol; Azimzadeh, Agnes M.; Ayares, David; Robson, Simon C.; Pierson, Richard N., III; Surgery, School of Medicine
    Barriers to successful lung xenotransplantation appear to be even greater than for other organs. This difficulty may be related to several macro anatomic factors, such as the uniquely fragile lung parenchyma and associated blood supply that results in heightened vulnerability of graft function to segmental or lobar airway flooding caused by loss of vascular integrity (also applicable to allotransplants). There are also micro-anatomic considerations, such as the presence of large numbers of resident inflammatory cells, such as pulmonary intravascular macrophages and natural killer (NK) T cells, and the high levels of von Willebrand factor (vWF) associated with the microvasculature. We have considered what developments would be necessary to allow successful clinical lung xenotransplantation. We suggest this will only be achieved by multiple genetic modifications of the organ-source pig, in particular to render the vasculature resistant to thrombosis. The major problems that require to be overcome are multiple and include (i) the innate immune response (antibody, complement, donor pulmonary and recipient macrophages, monocytes, neutrophils, and NK cells), (ii) the adaptive immune response (T and B cells), (iii) coagulation dysregulation, and (iv) an inflammatory response (e.g., TNF-α, IL-6, HMGB1, C-reactive protein). We propose that the genetic manipulation required to provide normal thromboregulation alone may include the introduction of genes for human thrombomodulin/endothelial protein C-receptor, and/or tissue factor pathway inhibitor, and/or CD39/CD73; the problem of pig vWF may also need to be addressed. It would appear that exploration of every available therapeutic path will be required if lung xenotransplantation is to be successful. To initiate a clinical trial of lung xenotransplantation, even as a bridge to allotransplantation (with a realistic possibility of survival long enough for a human lung allograft to be obtained), significant advances and much experimental work will be required. Nevertheless, with the steadily increasing developments in techniques of genetic engineering of pigs, we are optimistic that the goal of successful clinical lung xenotransplantation can be achieved within the foreseeable future. The optimistic view would be that if experimental pig lung xenotransplantation could be successfully managed, it is likely that clinical application of this and all other forms of xenotransplantation would become more feasible.
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    Coagulation factor IX gene transfer to non-human primates using engineered AAV3 capsid and hepatic optimized expression cassette
    (Elsevier, 2021-08-26) Kumar, Sandeep R. P.; Xie, Jun; Hu, Shilang; Ko, Jihye; Huang, Qifeng; Brown, Harrison C.; Srivastava, Alok; Markusic, David M.; Doering, Christopher B.; Spencer, H. Trent; Srivastava, Arun; Gao, Guangping; Herzog, Roland W.; Pediatrics, School of Medicine
    Hepatic gene transfer with adeno-associated viral (AAV) vectors shows much promise for the treatment of the X-linked bleeding disorder hemophilia B in multiple clinical trials. In an effort to further innovate this approach and to introduce alternative vector designs with potentially superior features into clinical development, we recently built a vector platform based on AAV serotype 3 because of its superior tropism for human hepatocytes. A vector genome with serotype-matched inverted terminal repeats expressing hyperactive human coagulation factor IX (FIX)-Padua was designed for clinical use that is optimized for translation using hepatocyte-specific codon-usage bias and is depleted of immune stimulatory CpG motifs. Here, this vector genome was packaged into AAV3 (T492V + S663V) capsid for hepatic gene transfer in non-human primates. FIX activity within or near the normal range was obtained at a low vector dose of 5 × 1011 vector genomes/kg. Pre-existing neutralizing antibodies, however, completely or partially blocked hepatic gene transfer at that dose. No CD8+ T cell response against capsid was observed. Antibodies against the human FIX transgene product formed at a 10-fold higher vector dose, albeit hepatic gene transfer was remarkably consistent, and sustained FIX activity in the normal range was nonetheless achieved in two of three animals for the 3-month duration of the study. These results support the use of this vector at low vector doses for gene therapy of hemophilia B in humans.
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    Correlation Analysis of Histopathology and Proteogenomics Data for Breast Cancer
    (American Society for Biochemistry and Molecular Biology, 2019-08-09) Zhan, Xiaohui; Cheng, Jun; Huang, Zhi; Han, Zhi; Helm, Bryan; Liu, Xiaowen; Zhang, Jie; Wang, Tian-Fu; Ni, Dong; Huang, Kun; Medicine, School of Medicine
    Tumors are heterogeneous tissues with different types of cells such as cancer cells, fibroblasts, and lymphocytes. Although the morphological features of tumors are critical for cancer diagnosis and prognosis, the underlying molecular events and genes for tumor morphology are far from being clear. With the advancement in computational pathology and accumulation of large amount of cancer samples with matched molecular and histopathology data, researchers can carry out integrative analysis to investigate this issue. In this study, we systematically examine the relationships between morphological features and various molecular data in breast cancers. Specifically, we identified 73 breast cancer patients from the TCGA and CPTAC projects matched whole slide images, RNA-seq, and proteomic data. By calculating 100 different morphological features and correlating them with the transcriptomic and proteomic data, we inferred four major biological processes associated with various interpretable morphological features. These processes include metabolism, cell cycle, immune response, and extracellular matrix development, which are all hallmarks of cancers and the associated morphological features are related to area, density, and shapes of epithelial cells, fibroblasts, and lymphocytes. In addition, protein specific biological processes were inferred solely from proteomic data, suggesting the importance of proteomic data in obtaining a holistic understanding of the molecular basis for tumor tissue morphology. Furthermore, survival analysis yielded specific morphological features related to patient prognosis, which have a strong association with important molecular events based on our analysis. Overall, our study demonstrated the power for integrating multiple types of biological data for cancer samples in generating new hypothesis as well as identifying potential biomarkers predicting patient outcome. Future work includes causal analysis to identify key regulators for cancer tissue development and validating the findings using more independent data sets.
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    Differential Infiltration of Key Immune T-Cell Populations Across Malignancies Varying by Immunogenic Potential and the Likelihood of Response to Immunotherapy
    (MDPI, 2024-12-03) Eljilany, Islam; Coleman, Sam; Tan, Aik Choon; McCarter, Martin D.; Carpten, John; Colman, Howard; Naqash, Abdul Rafeh; Puzanov, Igor; Arnold, Susanne M.; Churchman, Michelle L.; Spakowicz, Daniel; Salhia, Bodour; Marin, Julian; Ganesan, Shridar; Ratan, Aakrosh; Shriver, Craig; Hwu, Patrick; Dalton, William S.; Weiner, George J.; Conejo-Garcia, Jose R.; Rodriguez, Paulo; Tarhini, Ahmad A.; Medicine, School of Medicine
    Background: Solid tumors vary by the immunogenic potential of the tumor microenvironment (TME) and the likelihood of response to immunotherapy. The emerging literature has identified key immune cell populations that significantly impact immune activation or suppression within the TME. This study investigated candidate T-cell populations and their differential infiltration within different tumor types as estimated from mRNA co-expression levels of the corresponding cellular markers. Methods: We analyzed the mRNA co-expression levels of cellular biomarkers that define stem-like tumor-infiltrating lymphocytes (TILs), tissue-resident memory T-cells (TRM), early dysfunctional T-cells, late dysfunctional T-cells, activated-potentially anti-tumor (APA) T-cells and Butyrophilin 3A (BTN3A) isoforms, utilizing clinical and transcriptomic data from 1892 patients diagnosed with melanoma, bladder, ovarian, or pancreatic carcinomas. Real-world data were collected under the Total Cancer Care Protocol and the Avatar® project (NCT03977402) across 18 cancer centers. Furthermore, we compared the survival outcomes following immune checkpoint inhibitors (ICIs) based on immune cell gene expression. Results: In melanoma and bladder cancer, the estimated infiltration of APA T-cells differed significantly (p = 4.67 × 10-12 and p = 5.80 × 10-12, respectively) compared to ovarian and pancreatic cancers. Ovarian cancer had lower TRM T-cell infiltration than melanoma, bladder, and pancreatic (p = 2.23 × 10-8, 3.86 × 10-28, and 7.85 × 10-9, respectively). Similar trends were noted with stem-like, early, and late dysfunctional T-cells. Melanoma and ovarian expressed BTN3A isoforms more than other malignancies. Higher densities of stem-like TILs; TRM, early and late dysfunctional T-cells; APA T-cells; and BTN3A isoforms were associated with increased survival in melanoma (p = 0.0075, 0.00059, 0.013, 0.005, 0.0016, and 0.041, respectively). The TRM gene signature was a moderate predictor of survival in the melanoma cohort (AUROC = 0.65), with similar findings in testing independent public datasets of ICI-treated patients with melanoma (AUROC 0.61-0.64). Conclusions: Key cellular elements related to immune activation are more heavily infiltrated within ICI-responsive versus non-responsive malignancies, supporting a central role in anti-tumor immunity. In melanoma patients treated with ICIs, higher densities of stem-like TILs, TRM T-cells, early dysfunctional T-cells, late dysfunctional T-cells, APA T-cells, and BTN3A isoforms were associated with improved survival.
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    Efficacy of novel allogeneic cancer cells vaccine to treat colorectal cancer
    (Frontiers Media, 2024-07-24) Alzeeb, George; Tortorelli, Corinne; Taleb, Jaqueline; De Luca, Fanny; Berge, Benoit; Bardet, Chloé; Limagne, Emeric; Brun, Marion; Chalus, Lionel; Pinteur, Benoit; Bravetti, Paul; Gongora, Céline; Apetoh, Lionel; Ghiringhelli, Francois; Medicine, School of Medicine
    Colorectal cancer (CRC) remains a significant global health burden, emphasizing the need for innovative treatment strategies. 95% of the CRC population are microsatellite stable (MSS), insensitive to classical immunotherapies such as anti-PD-1; on the other hand, responders can become resistant and relapse. Recently, the use of cancer vaccines enhanced the immune response against tumor cells. In this context, we developed a therapeutic vaccine based on Stimulated Tumor Cells (STC) platform technology. This vaccine is composed of selected tumor cell lines stressed and haptenated in vitro to generate a factory of immunogenic cancer-related antigens validated by a proteomic cross analysis with patient's biopsies. This technology allows a multi-specific education of the immune system to target tumor cells harboring resistant clones. Here, we report safety and antitumor efficacy of the murine version of the STC vaccine on CT26 BALB/c CRC syngeneic murine models. We showed that one cell line (1CL)-based STC vaccine suppressed tumor growth and extended survival. In addition, three cell lines (3CL)-based STC vaccine significantly improves these parameters by presenting additional tumor-related antigens inducing a multi-specific anti-tumor immune response. Furthermore, proteomic analyses validated that the 3CL-based STC vaccine represents a wider quality range of tumor-related proteins than the 1CL-based STC vaccine covering key categories of tumor antigens related to tumor plasticity and treatment resistance. We also evaluated the efficacy of STC vaccine in an MC38 anti-PD-1 resistant syngeneic murine model. Vaccination with the 3CL-based STC vaccine significantly improved survival and showed a confirmed complete response with an antitumor activity carried by the increase of CD8+ lymphocyte T cells and M1 macrophage infiltration. These results demonstrate the potential of this technology to produce human vaccines for the treatment of patients with CRC.