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CAR-T cell therapy for liver metastasesLashtur, Nelya 03 November 2016 (has links)
Liver metastases are the most common cause of death in colorectal cancer patients. The standard of care and potential for cure for colorectal liver metastases is resection, but often times disease it too extensive for this treatment. Over the years, cancer research has made way for advances in treating progressive disease through immunotherapy. By genetically modifying an individual’s immune system using virally transduced chimeric antigen receptor T cells (CAR-T), patients are better able to receive exquisitely specific T cells to target specific tumors. Furthermore, selective delivery strategies may enhance efficacy while limiting detrimental, systemic adverse effects. Not only this, CAR-Ts have also lead to complete remission in some liquid tumors while maintaining the potential for remission in solid tumors as well. This literature review takes readers through the emergence of the different generations of CAR-T and the various studies including clinical trials that have demonstrated the safety and efficacy of CAR-T.
The second portion of this paper will outline the design for a phase II clinical trial using intrahepatic CAR-T therapy in addition to selective internal radiation therapy (SIRT) for refractory CEA+ colorectal liver metastases. Benefits and limitations of using these therapies are further discussed.
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VDJML: a file format with tools for capturing the results of inferring immune receptor rearrangementsToby, Inimary T., Levin, Mikhail K., Salinas, Edward A., Christley, Scott, Bhattacharya, Sanchita, Breden, Felix, Buntzman, Adam, Corrie, Brian, Fonner, John, Gupta, Namita T., Hershberg, Uri, Marthandan, Nishanth, Rosenfeld, Aaron, Rounds, William, Rubelt, Florian, Scarborough, Walter, Scott, Jamie K., Uduman, Mohamed, Vander Heiden, Jason A., Scheuermann, Richard H., Monson, Nancy, Kleinstein, Steven H., Cowell, Lindsay G. 06 October 2016 (has links)
Background: The genes that produce antibodies and the immune receptors expressed on lymphocytes are not germline encoded; rather, they are somatically generated in each developing lymphocyte by a process called V(D) J recombination, which assembles specific, independent gene segments into mature composite genes. The full set of composite genes in an individual at a single point in time is referred to as the immune repertoire. V(D) J recombination is the distinguishing feature of adaptive immunity and enables effective immune responses against an essentially infinite array of antigens. Characterization of immune repertoires is critical in both basic research and clinical contexts. Recent technological advances in repertoire profiling via high-throughput sequencing have resulted in an explosion of research activity in the field. This has been accompanied by a proliferation of software tools for analysis of repertoire sequencing data. Despite the widespread use of immune repertoire profiling and analysis software, there is currently no standardized format for output files from V(D) J analysis. Researchers utilize software such as IgBLAST and IMGT/High V-QUEST to perform V(D) J analysis and infer the structure of germline rearrangements. However, each of these software tools produces results in a different file format, and can annotate the same result using different labels. These differences make it challenging for users to perform additional downstream analyses. Results: To help address this problem, we propose a standardized file format for representing V(D) J analysis results. The proposed format, VDJML, provides a common standardized format for different V(D) J analysis applications to facilitate downstream processing of the results in an application-agnostic manner. The VDJML file format specification is accompanied by a support library, written in C++ and Python, for reading and writing the VDJML file format. Conclusions: The VDJML suite will allow users to streamline their V(D) J analysis and facilitate the sharing of scientific knowledge within the community. The VDJML suite and documentation are available from https:// vdjserver. org/ vdjml/. We welcome participation from the community in developing the file format standard, as well as code contributions.
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A natural killer cell-centric approach toward new therapeutics for autoimmune disease.Reighard, Seth D. 10 October 2019 (has links)
No description available.
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Targeting Tumour Antigen Heterogeneity with Dual-Specific Adoptive Cell TransferFisher, Robert January 2021 (has links)
Through the years, cancer therapies have progressed rapidly, pouring out novel treatments such as gene therapy, small molecule therapies and immunotherapy. One such immunotherapy, adoptive cell transfer (ACT), augmented through the addition of a chimeric antigen receptor (CAR), has proven success in treatment of hematological malignancies. Additionally, oncolytic viruses (OV) and OV-based (OVV) therapies, have shown promising results in both clinical and pre-clinical studies. In most instances, when applied as a monotherapy, the aforementioned treatment methods are incapable of inducing complete tumour remission. The Wan lab has developed an approach combining ACT with OVV therapies that dramatically increase therapeutic benefit resulting in complete regression of well-established solid tumours. Despite promising results, certain tumours can still escape this combination therapy through antigen loss resulting in antigen negative relapse (ANR). To further augment the therapy, the addition of a secondary receptor (CAR) provides the ACT multiple avenues of attack to prevent ANR. In this dissertation, we define culture conditions that promote strong expression of the CAR alongside confirmation of function in an in vitro setting. Following, it is demonstrated that OVV boosted dual-targeting T cells carry strong T cell activity by measure of cytokine release in vivo. Despite promising T cell activity data, dual-specific T cells are unable to improve tumour control and survival once relapse occurs. The failure to control relapse remains unclear however evidence points towards lack of T cell persistence, poor CAR function in vivo and a lack of endogenous T cell response leading to compounding effects that prevent dual-targeting T cells from preventing ANR. Although dual specific therapies have shown poor efficacy in preventing ANR, further study must be completed to identify areas of improvement – such as persistence, as the potential for success in using dual-targeting T cells coupled with OVVs still lies untapped. / Thesis / Master of Science (MSc)
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DEVELOPING A HIGH THROUGHPUT ASSAY TO INVESTIGATE CHEMICAL AGENTS WHICH SENSITIZE TUMOUR CELLS TO KILLING BY CAR ENGINEERED T CELLSTantalo, Daniela 11 1900 (has links)
Cancer immunotherapy is emerging as a powerful tool in the treatment of cancer. Multiple clinical trials have established that infusion of tumour-specific T cells can cause regression of advanced tumours and prevent tumour relapse. While tumour-specific T cells are typically rare, engineering methods have been developed to introduce tumour-specific receptors into T cells and engender peripheral blood T cells with the ability to kill tumour cells. These engineering successes notwithstanding, tumour cells demonstrate variable sensitivity to T cell attack. Therefore, to maximize the impact of the engineered T cells, it is necessary to develop therapeutic strategies that render tumour cells sensitive to immune attack. For my thesis research, I sought to develop a high throughput screening assay that would allow me to screen chemical libraries for agents that sensitize tumour cells to T cell attack. My ultimate goal is to define chemical agents that effectively sensitize tumour cells to T cell attack but display a better toxicity profile than existing chemotherapies. To this end, I developed a screen where resistant tumour cells were exposed to T cells engineered with chimeric antigen receptors and positive hits were defined as agents that could enhance killing of the tumour cells. My work explored both murine and human systems and I ultimately decided to use human cells for my screen. Multiple methods for measuring tumour cell killing were evaluated, many tumour lines were screened and I optimized the conditions for generating large numbers of engineered T cells for the screen. The net result of my thesis work is a miniaturized assay that is ready for high throughput screening. / Thesis / Master of Science in Medical Sciences (MSMS)
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Engineering biomaterial-enhanced therapeutics to control locally aggressive malignanciesBressler, Eric 19 July 2023 (has links)
At least 10% of all cancer deaths are attributable to local tumor disease burden. In select cases, existing treatments such as surgery, chemotherapy, radiation, and immunotherapy demonstrate efficacy in halting or slowing cancer progression to improve survival. However, these strategies remain insufficient for most patients depending on cancer stage and histological characteristics, resulting in locoregional spread, locoregional recurrence, or progression to metastatic disease while also inducing dose-limiting toxicity. Biomaterials enable localized delivery of small molecules and proteins to improve safety and efficacy of cancer therapies. To leverage the safety and efficacy of biomaterials for local cancer treatment, we developed electrospun, hydrophobic nanofiber meshes that deliver small molecules and proteins. The meshes are biodegradable, biocompatible, and mechanically robust, making them ideal delivery vehicles for intraoperative care in the context of local tumor resection. We optimized the meshes to deliver the chemotherapeutic doxorubicin via drug encapsulation within the nanofibers and within hydrophobic coatings made of poly(glycerol mono-stearate-co-caprolactone) (PGC-C18). The meshes, called doxorubicin-eluting meshes (DoMs), prevent local sarcoma recurrence while avoiding cardiotoxicity associated with systemic doxorubicin therapy. We next utilized this mesh formulation to encapsulate grazoprevir (GZV), an FDA approved drug recently repurposed as an inducer molecule for a logic chimeric antigen receptor (CAR) T cell. Using the meshes, we can modulate release over time and control cytokine expression in vitro. Finally, we designed meshes that adsorb proteins and release them in a tunable manner through wetting modulation, named ZipCAR Adaptor Modulation using a BiOdegradable Nanofiber Implant (ZAMBONI). We used the meshes to deliver universal CAR T cell adaptor proteins, which connect CAR T cells to cancer cells in a modular fashion. We demonstrate improved safety and efficacy in models of ovarian carcinoma and mesothelioma without evidence of on-target, off-tumor toxicity, a common mechanism of CAR T cell toxicity. Together, these results demonstrate a novel and robust approach to improve safety and efficacy in local cancer therapy. / 2025-07-19T00:00:00Z
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Relative hypercoagulation induced by suppressed fibrinolysis after tisagenlecleucel infusion in malignant lymphoma / 悪性リンパ腫に対するチサゲンレクルユーセル投与後に見られる線溶抑制および相対的凝固亢進状態Yamasaki(Morita), Makiko 24 November 2022 (has links)
京都大学 / 新制・課程博士 / 博士(人間健康科学) / 甲第24292号 / 人健博第107号 / 新制||人健||8(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 藤井 康友, 教授 岡 昌吾, 教授 滝田 順子 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM
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Capacity of Human Immunodeficiency Virus Targeting Chimeric Antigen Receptor T Cells to Eliminate Follicular Dendritic Cells Bearing Human Immunodeficiency Virus Immune ComplexesOllerton, Matthew T 01 December 2017 (has links)
An important obstacle to a functional cure for HIV/AIDS is the persistence of viral reservoirs found throughout the body in various cells and tissues. Reservoirs can be latently infected cells, or in the case of follicular dendritic cells (FDC), non-infected cells that trap infectious virus on their surface through immune complexes (HIV-IC). Although several strategies have been employed to target and eliminate viral reservoirs, they are short-lived and ineffective. In an attempt to provide a long-term approach, chimeric antigen receptor T (CAR-T) cells were designed to eliminate native HIV on FDCs. Although effective at eliminating HIV-infected cells, and halting spreading infection, their ability to eliminate the viral reservoir found on (FDCs) remains unclear. We used a novel second-generation CAR-T cell expressing domains 1 and 2 of CD4 followed by the mannose binding lectin (MBL) to allow recognition of native HIV envelope (Env) to determine the capacity to respond to the viral reservoir found on FDCs. We employed a novel fluorescent lysis assay, the Carboxyfluorescein succinimidyl ester (CFSE) release assay, as well as flow cytometric based assays to detect functional CAR-T activation through IFN-γ production and CD107a (i.e., LAMP1) membrane accumulation to test cytolytic capacity and functional activation of CD4-MBL CAR-T cells, respectively. We demonstrated their efficacy at eliminating HIV-infected cells or cells expressing gp160. However, these CAR-T cells were unable to lyse cells bearing surface bound HIV-IC. We found that failed lysis was not a unique feature of a resistant target, but a limitation in the CAR-T recognition elements. CAR-T cells were inactive in the presence of free HIV or in the presence of concentrated, immobilized virus. Further experiments determined that in addition to gp120 recognition by the CAR-T, the adhesion molecule ICAM-1 was necessary for efficient CAR-T cell killing of HIV-infected cells. CAR-T cell activity and killing were inhibited in the presence of ICAM-1 blocking antibody. These results suggest that other factors, such as adhesion molecules, play a vital role in CAR-T responses to HIV-infected cells. In addition, our findings highlighted the necessity to consider all models of HIV reservoirs, including FDCs, when evaluating therapeutic efficacy.
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Capacity of Human Immunodeficiency Virus Targeting Chimeric Antigen Receptor T Cells to Eliminate Follicular Dendritic Cells Bearing Human Immunodeficiency Virus Immune ComplexesOllerton, Matthew T 01 December 2017 (has links)
An important obstacle to a functional cure for HIV/AIDS is the persistence of viral reservoirs found throughout the body in various cells and tissues. Reservoirs can be latently infected cells, or in the case of follicular dendritic cells (FDC), non-infected cells that trap infectious virus on their surface through immune complexes (HIV-IC). Although several strategies have been employed to target and eliminate viral reservoirs, they are short-lived and ineffective. In an attempt to provide a long-term approach, chimeric antigen receptor T (CAR-T) cells were designed to eliminate native HIV on FDCs. Although effective at eliminating HIV-infected cells, and halting spreading infection, their ability to eliminate the viral reservoir found on (FDCs) remains unclear. We used a novel second-generation CAR-T cell expressing domains 1 and 2 of CD4 followed by the mannose binding lectin (MBL) to allow recognition of native HIV envelope (Env) to determine the capacity to respond to the viral reservoir found on FDCs. We employed a novel fluorescent lysis assay, the Carboxyfluorescein succinimidyl ester (CFSE) release assay, as well as flow cytometric based assays to detect functional CAR-T activation through IFN-γ production and CD107a (i.e., LAMP1) membrane accumulation to test cytolytic capacity and functional activation of CD4-MBL CAR-T cells, respectively. We demonstrated their efficacy at eliminating HIV-infected cells or cells expressing gp160. However, these CAR-T cells were unable to lyse cells bearing surface bound HIV-IC. We found that failed lysis was not a unique feature of a resistant target, but a limitation in the CAR-T recognition elements. CAR-T cells were inactive in the presence of free HIV or in the presence of concentrated, immobilized virus. Further experiments determined that in addition to gp120 recognition by the CAR-T, the adhesion molecule ICAM-1 was necessary for efficient CAR-T cell killing of HIV-infected cells. CAR-T cell activity and killing were inhibited in the presence of ICAM-1 blocking antibody. These results suggest that other factors, such as adhesion molecules, play a vital role in CAR-T responses to HIV-infected cells. In addition, our findings highlighted the necessity to consider all models of HIV reservoirs, including FDCs, when evaluating therapeutic efficacy.
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Characterization of a Novel Third-Generation Anti-CD24-CAR against Ovarian CancerKlapdor, Rüdiger, Wang, Shuo, Morgan, Michael, Dörk, Thilo, Hacker, Ulrich, Hillemanns, Peter, Büning, Hildegard, Schambach, Axel 25 January 2024 (has links)
Novel therapeutic approaches against ovarian cancer (OC) are urgently needed because of
its high rate of recurrence even after extensive surgery and multi-agent chemotherapy. We aimed
to develop a novel anti-CD24 chimeric antigen receptor (CAR) as an immunotherapeutic approach
against OC cells and cancer stem cells (CSC). CSC represents a subpopulation of the tumor
characterized by enhanced chemoresistance as well as the increased capability of self-renewal and
metastasis. We designed a codon-optimized third-generation CAR containing the highly active
single chain variable fragment (scFv) “SWA11” against CD24. We equipped the human NK-cell
line NK-92 with the anti-CD24 CAR and an anti-CD19 control CAR using lentiviral transduction.
Engineered NK-92 cells showed high cytotoxic activity against CD24-positive OC cell lines (SKOV3,
OVCAR3). This effect was restricted to CD24-expressing cells as shown after lentiviral transduction
of CD24-negative cell lines (A2780, HEK-293T) with CD24 transmembrane proteins. Additionally,
NK-92 cells equipped with our novel anti-CD24 CAR were highly effective against patient-derived
primary ovarian cancer cells. The activation of NK cells was shown by specific IFN
secretion
upon antigen stimulation. To further reduce possible off-target effects in vivo, we applied a
dual-CAR approach using an anti-CD24-CD28-41BB fusion protein linked via a 2A sequence to an
anti-mesothelin-CD3-CAR. The dual-CAR was simultaneously active against CD24 and mesothelin
expressing cells. Our novel anti-CD24-CAR showed a highly cytotoxic effect against OC cell lines and
primary OC cells and will be evaluated in future in vivo trials as a promising immunotherapeutic
approach against OC.
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