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Dissertations / Theses on the topic 'Immunotherapy'
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1
Dadi, C. N. "Cancer immunotherapy." Thesis, Sumy State University, 2015. http://essuir.sumdu.edu.ua/handle/123456789/40532.
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Over the years we have resorted to radiation, chemotherapy
and surgery in fighting cancer. Unlike the latter mentioned forms of
therapy cancer immunotherapy is one of the more recent approaches.
Cancer immunotherapy focuses on enhancing the body‘s immune
system in fighting cancer.
2
Ferrell, Melissa Leann. "Sublingual Immunotherapy." Diss., The University of Arizona, 2015. http://hdl.handle.net/10150/565918.
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One of the most common reasons people seek primary care and emergency care is to reduce the symptoms of allergies, such as hay fever. To meet this high demand, several recent FDA-approved methods for treating seasonal and perennial allergies have been developed, including sublingual immunotherapy tablets. Furthermore, no longer must a patient endure allergy shots; this can now be delivered sublingually. Although this method has been shown to have high safety and efficacy, very few clinicians actually utilize this form of therapy. The purpose of this paper is describe the use of sublingual immunotherapy among Nurse Practitioners (NPs) and discuss barriers that may prevent its use. Nurse Practitioners working in primary care settings were surveyed regarding their use of sublingual immunotherapy. Although many nurse practitioners treat patients with allergic disease, not one participant reported using sublingual immunotherapy. This discussion outlines some of the reasons NPs are not currently utilizing this method of allergy treatment and the findings are compared with the extant literature. This paper culminates in an evidence-based algorithm to outline best practices for utilizing sublingual immunotherapy to reduce allergy symptoms.
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Walker, Samantha Mary. "Immunotherapy for summer hayfever." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248036.
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Michael, Agnieszka. "Genetic immunotherapy for cancer." Thesis, St George's, University of London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437318.
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Kwan, Byron H. (Byron Hua). "Integrin-targeted cancer immunotherapy." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/104220.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2016.Cataloged from PDF version of thesis.
Includes bibliographical references.
Integrins are a family of heterodimeric cell surface receptors that are functionally important for cell adhesion, migration and proliferation. Certain integrins, especially those that are known to recognize the arginine-glycine-aspartate (RGD) motif, are heavily overexpressed in many cancers relative to healthy tissue, making them attractive targets for therapeutic intervention. However, prior attempts to antagonize these integrins as a cancer therapy have all failed in the clinic. In this thesis, we instead exploit integrins as a target tumor antigen in the context of immunotherapy. The engineered cysteine knot peptide, 2.5F, is highly crossreactive and capable of recognizing multiple RGD-binding integrins. Our initial attempts to utilize this binder as a targeting moiety for delivering IL-2 as an immunocytokine failed. Mathematical modeling results indicated that immunocytokines, unless adhering to specific design criteria, are unlikely to benefit from targeting and may actually exhibit limited efficacy. Therefore, we "deconstructed" this immunocytokine into its functional parts: extended half-life IL-2 and 2.5F-Fc, the antibody-like construct directed against RGD-binding integrins. This combination immunotherapeutic approach was able to synergistically control tumor growth in three syngeneic murine models of cancer, including durable cures and development of immunological memory. Contrary to prior attempts at integrin-targeting, the mechanism of action was independent of functional integrin antagonism, including effects on angiogenesis and tumor proliferation. In fact, efficacy of this therapy depended solely upon the adaptive and innate arms of immunity, specifically CD8+ T cells, macrophages, and dendritic cells. Furthermore, checkpoint blockade, the gold standard for immunotherapy to date, can further enhance the efficacy of this therapeutic approach. This signifies that the combination of IL-2 and 2.5F-Fc exerts a distinct, yet complementary immune response that opens the door for clinical translation.
by Byron H. Kwan.
Ph. D.
6
Harrison, Simon James. "Immunotherapy in multiple myeloma." Thesis, University of Glasgow, 2005. http://theses.gla.ac.uk/1054/.
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The BDCA antibodies allowed reliable measurement of dendritic cell (DC) subsets and B cell numbers in the blood of normal subjects, and patients with MM throughout the disease course. The numbers of blood myeloid DC (BmDC) and blood plasmacytoid DC (BpDC) are low throughout the course of the disease, and only improve for a short period of time following autologous HSCT. Thalidomide therapy of patients with relapsed disease was associated with an increase in BmDC1 and BpDC numbers. Monocytes, mobilised at the time of stem cell collection, were used to produce mature DC (matDC) from MM patients and normal donors (ND). The matDC produced from MM patients were of poorer quality as compared to those from ND, despite using combinations of GM/IL-4, GM/IL-13, X4 and MIMIC in the production process. The combinations that contained the X4 maturation cocktail produced the best quality matDC. The DC/T cell system is abnormal in MM patients. Despite this, it is possible to produce antigen loaded mature MoDC from MM patients. When combined with T cell pre-stimulation and IL-2 expansion, these DC are capable of inducing anti-MM cytotoxic T cells, which exhibit considerable anti-MM cytolytic activity. However, the DC from MM patients still display abnormal chemokine receptor expression, which may inhibit their capability to migrate to lymph nodes in-vivo in order to generate these cytotoxic T cell responses. These observations will aid in the optimisation of DC based immune therapies for MM, and suggest that a combined immunotherapy approach using pre-stimulated T cells, MM Ag primed DC and IL-2 may produce better clinical responses in MM patients.
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Jain, Renu Zaghouani Habib. "Immunotherapy for autoimmune diabetes." Diss., Columbia, Mo. : University of Missouri-Columbia, 2008. http://hdl.handle.net/10355/6869.
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The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from PDF of title page (University of Missouri--Columbia, viewed on April 1, 2010). Vita. Thesis advisor: Habib Zaghouani. "May 2008" Includes bibliographical references.
8
Champiat, Stéphane. "Caractérisation clinique et biologique de l’hyperprogression tumorale lors du blocage de la voie PD-1/PD-L1." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS040.
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Les anticorps bloquant les points de contrôle immunitaires modifient profondément la gestion des patients atteints de cancer. À la pointe de cette nouvelle classe d'agents anticancéreux, les anticorps anti-PD-1 / PD-L1 peuvent ainsi restaurer une réponse efficace des cellules T antitumorales. En conséquence, ces agents sont maintenant approuvés dans divers types de tumeurs, tels que le mélanome, le cancer bronchique non à petites cellules, le cancer du rein, les tumeurs ORL ou le cancer de la vessie. Ces nouvelles immunothérapies entraînent également de nouveaux profils de réponse tumorale tels que des réponses tumorales retardées ou des pseudoprogressions. Au fil de l’expérience acquise avec ces traitements, il a été observé chez certains patients un état de progression rapide de la maladie, ce qui pourrait suggérer que le blocage de points de contrôle immunitaire pourrait avoir un effet délétère en accélérant la maladie chez un sous-groupe de patients. Ce travail de thèse a permis de caractériser sur le plan clinique et biologique ce phénomène d’accélération de la croissance tumorale sous immunothérapie anti-checkpoint que nous avons définit “maladie hyperprogressive” (HPD). L’analyse transcriptomique d’échantillons tumoraux de ces patients a permis d’orienter vers un rôle spécifique de l’environnement myeloideImmune checkpoint blocking antibodies are profoundly changing the management of patients with cancer. At the forefront of this novel anticancer agent class, anti-PD-1/PD-L1 antibodies can exhibit a significant activity by restoring an efficient antitumor T-cell response. As a result, these agents are now approved in various tumor types such as melanoma, squamous, and nonsquamous non–small cell lung cancer (NSCLC), renal cell carcinoma (RCC), head and neck squamous cell carcinoma (HNSCC) or bladder cancer. Interestingly, these new immunotherapies also result in novel tumor response patterns such as delayed tumor responses or pseudoprogressions. As experience grows with these therapeutics, anecdotal reports are relating rapid disease progressions, which could suggest that immune checkpoint blockade may have a deleterious effect by accelerating the disease in a subset of patients. This thesis work has made it possible to characterize clinically and biologically this phenomenon of accelerated tumor growth under anti-checkpoint immunotherapy, which we have defined as “hyperprogressive disease” (HPD). Transcriptomic analysis of tumour samples from these patients suggested a specific role for the myeloid environment
9
Bracher, Marguerite. "IgE in immunotherapy of cancer." Thesis, King's College London (University of London), 2006. https://kclpure.kcl.ac.uk/portal/en/theses/ige-in-immunotherapy-of-cancer(08abceea-54a8-436c-9504-24742d57538d).html.
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Graff, Christilyn Paula. "Antibody engineering for tumor immunotherapy." Thesis, Massachusetts Institute of Technology, 2002. http://hdl.handle.net/1721.1/29279.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2002.Vita.
Includes bibliographical references (leaves 130-140).
Antibodies have been used as cancer therapeutics for several decades. One area in which this therapy may be improved is the retention time of antibody in the tumor relative to normal tissue. In this Thesis, we have attempted to elucidate the mechanisms that are most influential to improving antibodies as cancer therapeutics. Carcinoembryonic antigen (CEA) has long been identified as a tumor-associated antigen. CEA is also quite stable, with a cell-surface shedding half-life of approximately 7 days. Directed evolution methodology has been utilized to design an antibody fragment with properties that would improve tumor retention. Specifically, antibody engineering methods were used to produce a humanized, extremely high affinity and stable single chain antibody fragment (scFv) against CEA. Several mutant scFv libraries were constructed and screened against soluble CEA with yeast surface display and fluorescent activated cell sorting (FACS). A series of antibodies were engineered that span three orders of magnitude in off-rate improvement. These antibody fragments show excellent stability at physiologically relevant temperatures. In addition, soluble protein expression levels were greatly improved. The final product has a dissociation half-life of approximately 7 days, currently the longest engineered half-life of an scFv against a tumor-associated antigen. Binding and diffusion in micrometastases was also modeled to gain an improved understanding of the quantitative interplay among the rate processes of diffusion, binding, degradation, and plasma clearance in tumor microspheroids.
(cont.) Modeling studies illuminated the importance of targeting stable tumor-associated antigens. The elimination rate of the antigen was of critical importance to the change in the therapeutic effect of antibodies with increasing affinity. The significance of this result in the context of previous experimental studies will be discussed. By affinity maturing an antibody with a dissociation half-life equal to the turnover half-life of the antigen, we have engineered an antibody with effectively irreversible binding to CEA. Differences in retention for the series of scFvs will thus be dominated by the off-rate of the antibody and not the half-life of CEA. With this in mind, the molecules designed in this study can be used to reconcile the issue of affinity's impact on efficacy in tumor therapy.
by Christilyn Paula Graff.
Ph.D.
11
Opel, Cary F. (Cary Francis). "T cell mediated combination immunotherapy." Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/107075.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, February 2016.Cataloged from PDF version of thesis. "September 2015."
Includes bibliographical references (pages 128-131).
Immunotherapy is a broad treatment strategy that harnesses the immune system to fight off a particular condition or disease. Cancer immunotherapy is the specific application of agents designed to interact or stimulate the immune system to fight off tumors. Treatments as diverse as passive antibody therapy, cytokine support, and comprehensive adoptive T cell transfer make up the broad field of immunotherapeutics. Due to the naturally complex interactions inherent in the immune system, there are many options for therapeutic intervention, however, this same complexity makes it extremely difficult to optimize treatment strategies. Because of this, research into developing new immunotherapies, optimizing existing immunotherapies, and designing new combinations of immunotherapies is still critical in the fight against cancer. Although there have been ongoing successes of individual immunotherapies in the clinic, the complexity and interdependence of the immune system suggests that any single therapeutic intervention will be insufficient to reject established malignancies. Increased interest in applying combinations of immunotherapies in the clinic requires more thorough preclinical work to guide the designs of these studies. The work presented in this thesis focuses on developing combinations of immunotherapies to treat preclinical models of cancer, as well as studying the underlying mechanism of tumor control. T cells are potent mediators of cytotoxicity and when properly used in adoptive cell transfer (ACT) protocols, can be highly effective in the treatment of cancer. ACT consists of three steps: 1) harvesting and purifying T cells from the patient, 2) enriching or modifying the T cells to become tumor specific, and 3) reinfusing the T cells along with supporting therapies. Therapies given alongside ACT are often adjuvants designed to enhance T cell response. However, focusing therapies only on enhancing the activity of the transferred T cells may miss out on synergistic effects when other parts of the immune system are simultaneously engaged. To study the effect of adjuvant therapy on ACT, a preclinical murine model was analyzed. Large, established B16F10 tumors were controlled when pmel-1 T cells were given with a course of supportive MSA-IL2 cytokine therapy, however, no cures were observed. When a course of TA99 antibody therapy was added alongside ACT, a high rate of cures was observed. Flow cytometry of both circulating and tumor infiltrating pmel-1 cells showed massive expansion and activation. Additionally, tumor infiltration of neutrophils, NK cells, and DCs were greatly enhanced by adjuvant therapy. DCs in the tumor draining lymph nodes were largely unchanged by the therapies. Engagement of the humoral immune response was also observed in both treatment cases. Surprisingly, antibody therapy did not substantially alter any of the mechanistic observations made in this study, despite its critical role in achieving cures of tumors. While ACT is a highly effective therapy, its clinical applicability is hindered by the complexity of performing T cell transplants and manipulations. A more optimal solution would involve purely injectable treatments that could elicit the same level of tumor specific T cell response in conjunction with potent recruitment of the adaptive immune system against tumors. To achieve this, working in collaboration with the Irvine Lab, combinations of immunotherapy using up to four different components were tested to identify critical factors in the successful rejection of established tumors in preclinical models. The four components of tumor targeting antibody, cytokine support, checkpoint blockade, and cancer vaccine acted synergistically to reject tumors from B16F10, TC-1, and DD-Her2/neu cell lines. The cancer vaccine elicited large numbers of tumor-specific T cells, and acted as a replacement for ACT. By analyzing subset combinations of this full treatment, the roles of each therapeutic component were identified. CD8 T cells and cross-presenting DCs were critical to curing subcutaneous tumors. Cytokine therapy was indispensable for effective tumor control, promoted immune cell infiltration into the tumor, and led to an increase in DCs. In combination with the other therapies, vaccination against a tumor antigen elicited a strong immunological memory response that was able to reject subsequent tumor rechallenge, as well as promote antigen spreading to new epitopes. Successful combinations were demonstrated to be dependent on the recruitment of both the adaptive and innate branches of the immune system. Finally, the efficacy of this combination of treatments was demonstrated by controlling the growth of induced tumors in a BRaf/Pten model. Combination immunotherapy promises a future where synergistic treatments are specifically tailored to individual cancers leading to highly effective responses. However, determining the optimal combination of therapies, the complexity of dosing strategies, and the availability of targeted treatments are all barriers that must be overcome. The analysis presented here will make a significant contribution to the body of knowledge on immunotherapy as it has shown the importance of combining orthogonal immunotherapies in order to get durable cures to established tumors. These results will hopefully encourage combinations of orthogonally acting therapies based on T cells to achieve stronger clinical responses. By determining the necessary requirements for a strong, synergistic response to tumorous growths, more effective combination immunotherapy protocols may be designed in the future.
by Cary F. Opel.
Ph. D.
12
Barker, Susanne Elizabeth. "Cellular immunotherapy for murine neuroblastoma." Thesis, University College London (University of London), 2004. http://discovery.ucl.ac.uk/1446885/.
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Neuroblastoma (NB) is the most common extracranial paediatric tumour, and patients with disseminated disease have a poor long-term prognosis. Due to the significant mortality rate, alternative treatments to conventional therapies are continually sought. Using the A/J mouse model it has previously been demonstrated that a cellular vaccine of the syngeneic Neuro-2a NB cell line modified to express IL-2 and IL-12 abrogated the tumourigenicity of Neuro-2a cells, and mediated regression of established tumours. However, establishing cultures of primary NB cells can be problematic, making this approach difficult to implement clinically. This thesis describes the development of an alternative cellular vaccine to treat murine NB using a synthetic vector. Firstly, transfection of primary dendritic cells was optimised. Dendritic cells are potent antigen presenting cells and studies have shown them to generate anti-cancer responses. Optimal transfection levels of 5% were obtained but antigen presentation by these cells was limited. Therefore, an alternative approach was developed using fibroblasts engineered to express IL-2 and IL-12. Cytokine-expressing fibroblasts could be used in place of transfected tumour cells to provide sustained, high-level cytokine expression in the tumour locale. Transfection of syngeneic and allogeneic murine fibroblasts was optimised in vitro to produce therapeutic levels of IL-2 and IL-12. Cytokine-transfected fibroblasts were compared with cytokine-transfected Neuro-2a cells to prevent engraftment of wild-type Neuro-2a cells in vivo. The allogeneic cells prevented tumour engraftment in a nonspecific, cytokine-independent manner. Syngeneic fibroblasts expressing IL-2 and IL-12 inhibited tumour engraftment as effectively as cytokine expressing Neuro-2a cells, and this rejection was cytokine-dependent. The cytokine-transfected syngeneic fibroblasts induced protective immunity against rechallenge with wild-type Neuro-2a cells as effectively as cytokine-transfected-Neuro-2a cells. Intratumoural vaccination of cytokine-transfected syngeneic fibroblasts also demonstrated therapeutic efficacy against Neuro-2a-derived established tumours. Splenocytes from vaccinated mice demonstrated increased IL-2 and IFN-y expression and cytotoxicity compared with controls when co-cultured with wild-type Neuro-2a cells in vitro. Vaccinated tumours showed decreased vascularity and increased infiltration of CD45+ cells compared with controls. Therefore, cytokine-transfected syngeneic fibroblasts are a viable potential alternative vaccine for the treatment of minimal residual NB.
13
Al, Kamal Nasrah Ali. "Immunotherapy for human breast cancer." Wright State University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=wright1452814566.
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Lundberg, Kajsa. "On immunotherapy against prostate cancer." Stockholm : Karolinska institutet, 2010. http://diss.kib.ki.se/2010/978-91-7409-805-1/.
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Vicario, Rocío. "Immunotherapy against HER2-positive breast cancers." Doctoral thesis, Universitat Autònoma de Barcelona, 2016. http://hdl.handle.net/10803/400279.
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El 20% de los tumores mamarios sobre expresan el receptor de
tirosina quinasa HER2, debido a su amplificación génica, tanto dentro de los
cromosomas (HSR) como fuera ellos (DM). Se sabe muy poco acerca de la
respuesta clínica o el rol en resistencia a terapias de estos patrones de
amplificación. Por otro lado, un porcentaje de pacientes HER2+ expresa
fragmentos carboxyl-terminales de HER2, p95HER2. Mas de la mitad de
pacientes HER2+ no responde a las terapias disponibles. Hasta el momento, se
desconoce si p95HER2 puede ser un blanco terapéutico. En este trabajo
estudiaremos resistencias a terapias anti-HER2 y desarrollaremos nuevas
terapias para el tratamiento de tumores p95HER2/HER2+.
En esta tesis, evaluamos si el patrón de amplificación tiene impacto en la
respuesta terapéutica. Mostramos que el ~30% de los tumores HER2+ tienen
amplificación en DM pero responden a la terapia de la misma manera que los
HSR. El número de DM se mantiene cuando se desarrolla resistencia a la terapia,
incluso si se pierde expresión proteica de HER2. Por lo tanto, la perdida de DM no
parece ser un mecanismo de resistencia a terapias anti-HER2.
Por otro lado, también evaluamos si p95HER2 puede ser un blanco para
inmunoterapia. Presentamos un anticuerpo bi-especifico de células T (p95-TCB)
que se une a p95HER2 en la célula tumoral y a CD3e, miembro del receptor de
células T, presente en linfocitos T. La unión simultanea a la célula tumoral y a la
célula T induce la activación de la célula T, la secreción de gránulos citotóxicos y
la lisis de la célula tumoral. En modelos pre-clínicos, mostramos que p95-TCB
aumenta la infiltración de células T y promueve la regresión tumoral. Comparado
con HER2-TCB, p95-TCB tiene la ventaja de discriminar las células normales con
baja expresión de HER2 previniendo efectos colaterales.
En resumen, este trabajo descarta a los DMs como predictores de respuesta a
terapias anti-HER2, y describe un nuevo anticuerpo bi-especifico que recluta y
active células inmunes a los tumores p95HER2/HER2+ y como consecuencia la
regresión de los mismos.Twenty percent of breast tumors are characterized by the overexpression of the receptor tyrosine kinase HER2, due to amplification of the gene, either within the chromosome (HSR) or outside as extrachromosomal entities (DM). Little is known about the clinical outcome or role in therapy resistance associated with these patterns of amplification. Furthermore, a proportion of HER2+ patients also express carboxyl terminal fragments of HER2, p95HER2. More than half of the patients do not respond to the current available anti-HER2 therapies. It is not yet known whether p95HER2 can be a therapeutic target. Therefore this dissertation is focused on the study of resistance to HER2- therapies and the development of new therapies for the treatment of p95HER2/HER2+ tumors. In this work we address whether the pattern of HER2 amplification impacts therapeutic response. We show that ~30% of HER2-positive tumors show amplification in DMs but respond equally to trastuzumab as HSR tumors. The number of DMs containing HER2 is maintained upon therapy resistance, even when the acquisition of resistance is concomitant with loss of HER2 protein expression. Thus, loss of DMs containing HER2 is not a likely mechanism of resistance to anti-HER2 therapies. In this thesis we also evaluate p95HER2 as a target for immune therapy for p95HER2/HER2+ patients. We present a T cell bispecific antibody (p95-TCB) that binds p95HER2 and CD3e, a subunit of the T cell receptor (TCR) present on T lymphocytes. Simultaneous binding of p95-TCB to tumor and T cells leads to T-cell activation, secretion of cytotoxic granules, and tumor cell lysis. In pre-clinical models we showed that p95-TCB increases immune cell infiltration and promotes tumor regression. Compared to classical HER2-TCB, p95-TCB has the potential advantage of sparing normal tissues with low HER2 expression from undesired killing. In summary, this work rules out the role of DMs as clinical predictors to anti-HER2 therapy, and describes a novel bispecific antibody that recruits immune cells to p95HER2/HER2+ tumors and consequently counteracts tumor growth.
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Wurzenberger, Cornelia. "Dendritic cell vaccines in tumor immunotherapy." Diss., lmu, 2009. http://nbn-resolving.de/urn:nbn:de:bvb:19-95530.
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Young, James Graham. "Gene & immunotherapy of prostate cancer." Thesis, University of Birmingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289297.
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Nani, Frank Kofi. "Mathematical models of chemotherapy and immunotherapy." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape15/PQDD_0012/NQ34816.pdf.
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Karlsson, Mona. "Sentinel node based immunotherapy of cancer /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-203-3/.
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Vikman, Sofia. "Towards Immunotherapy of Midgut Carcinoid Tumors." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Universitetsbiblioteket [distributör], 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8421.
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Bokaee, Shadi. "Trageting homeobox genes for cancer immunotherapy." Thesis, University of Surrey, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.543286.
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Thrower, Sally L. "Peptide immunotherapy in type 1 diabetes." Thesis, University of Bristol, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546202.
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Linardakis, Emmanouela. "Developing immunotherapy strategies for cancer treatment." Thesis, Open University, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.396819.
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Tabbah, Khaldoun. "Specific immunotherapy for perennial allergic rhinitis." Thesis, University of Southampton, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299414.
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Mussai, Francis Jay. "Immunotherapy and immunomodulation for haematological malignancies." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:6120e659-0dab-4447-b4d6-75e235d3b2c8.
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HA22 is an immunotoxin composed of an anti-CD22 variable fragment linked to a 38 kDa truncated protein derived from Pseudomonas exotoxin A. The mechanisms of cytotoxicity and resistance of HA22 against Acute Lymphoblastic Leukaemia (ALL) and Burkitt’s lymphoma were studied. Using a bone marrow mesenchymal cell culture assay to support ALL cell viability, I? investigated the in vitro cytotoxicity of HA22 against ALL blasts from newly diagnosed and relapsed patients. There was interpatient variability in sensitivity to HA22. There was no significant difference in HA22 sensitivity between diagnosis and relapse samples but peripheral blood ALL blasts were more sensitive to HA22 than those from bone marrow. The mechanisms of resistance to HA22 were studied, using cell lines as a model. The number of CD22 sites/ cell and the rates of immunotoxin internalisation did not affect HA22 cytotoxicity. HA22 mutants with resistance to lysosomal degradation and enhanced targeting to the endoplasmic reticulum had improved cytotoxicity. The role of apoptosis pathways proteins in HA22-mediated cell death was studied. Their role is complex but raised levels of the anti-apoptotic pathway protein Bcl-2 were found in the most resistant NALM6 cell line. Penetration of HA22 into Burkitt’s lymphoma masses was studied using a flow cytometric based method. HA22 rapidly penetrated into the lymphoma masses, however a barrier to further uptake is present which could not be overcome by the addition of adriamycin or taxol in the murine xenograft model. The ability of Acute Myeloid Leukaemia (AML) blasts to create an immunosuppressive niche was investigated using a cell line model and primary patient samples. AML blasts suppress T cell proliferation through altered arginine metabolism, dependent on the enzymes arginase II and iNOS. Small molecule inhibitors to arginase and iNOS restored T cell proliferation in vitro. AML further enhances its immunosuppressive niche by transforming surrounding monocytes into an M2-immunosuppressive phenotype, in an arginase dependent manner. The immunomodulatory protein Serum Amyloid A (SAA) was secreted by AML blasts, and leads to AML chemotaxis, IL-1production, and release of S100A9 protein. Finally, invariant Natural Killer T cells (iNKT) were shown to be cytotoxic to some AML blasts, in the presence of Galactosylceramide, and thus able to restore T cell proliferation. The results provide a strong rationale for the clinical testing of these novel immunotherapeutic and immunomodulatory strategies in patients with haematological malignancies.
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Schroeder, Sulana K. "Tau-Directed Immunotherapy for Alzheimer's Disease." Thesis, University of South Florida, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10264596.
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Alzheimer’s disease (AD) is the leading cause of dementia, accounting for 50 to 80 percent of dementia cases, and the prevalence of the disease is projected to increase significantly with time. AD is characterized by severe cognitive decline with age, ultimately requiring continued caregiving and eventually death. The pathology of AD is characterized by the presence of extracellular amyloid plaques, intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein, neuron loss, and evidence of inflammation indicated by the presence of reactive microglia and astrocytes. Frontotemporal Lobe Dementia (FTLD) is a rare form of dementia that is related to AD, most notably in the pathology of hyperphosphorylated tau and macroscopic brain shrinkage. It has been defined as one of a host of tauopathies, and has a more rapid onset than AD. Symptoms that resemble personality changes, moreso than memory loss, are characteristic of these other tauopathies (FTLD is a representative of a whole class of neurological disorders). Like AD, there are no known treatments or cures for FTLD. AD and FTLD are two manifestations of a class of diseases known as tauopathies, due to the presence of toxic forms of tau.
Tau is a protein normally found in neurons. It functions as a stabilizer for microtubules, and has a role in the trafficking of materials from the cell body to the presynaptic terminal. In AD and FTLD, tau can become hyperphosphorylated, which causes it to form twisted fibrils called NFTs. An emerging area of research is to identify antibodies that target tau as a way to clear tau pathology and hopefully reduce synaptic and neuron loss (Boutajangout et al., 2011b). While these diseases have no known cure or treatment at present, immunotherapy is emerging as a promising approach for treatment. The studies presented here investigated a variety of antibodies directed against tau, and incorporated different timeframes and administration routes to identify the best candidate for future clinical investigation of tau immunotherapy.
The mouse model rTg4510, known for expressing cognitive-related tauopathy, was primarily used to evaluate tau antibody effectiveness prior to clinical consideration. Our investigations began by utilizing a more familiar mouse which was also reported to express tau pathology.
Our studies first examined intracranial injection of a variety of antibodies using a mouse model previously reported to demonstrate tau pathology, to identify short-term clearance of tau pathology and NFTs. Next, we examined a more robust tau-producing mouse line, to further identify a most effective antibody, as well as to examine the time course of effect, after administration. A longer-term administration, and different route of administration was tested using mini-osmotic pump implantation into the mice, which provided for 28-day continuous infusion. This approach was followed with administration of antibodies, systemically. Behavioral analysis, in addition to pathological testing, was incorporated into the longer-term administration studies.
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Schroeder, Sulana Kay. "Tau-Directed Immunotherapy for Alzheimer’s Disease." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6757.
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Alzheimer’s disease (AD) is the leading cause of dementia, accounting for 50 to 80 percent of dementia cases, and the prevalence of the disease is projected to increase significantly with time. AD is characterized by severe cognitive decline with age, ultimately requiring continued caregiving and eventually death. The pathology of AD is characterized by the presence of extracellular amyloid plaques, intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein, neuron loss, and evidence of inflammation indicated by the presence of reactive microglia and astrocytes. Frontotemporal Lobe Dementia (FTLD) is a rare form of dementia that is related to AD, most notably in the pathology of hyperphosphorylated tau and macroscopic brain shrinkage. It has been defined as one of a host of tauopathies, and has a more rapid onset than AD. Symptoms that resemble personality changes, moreso than memory loss, are characteristic of these other tauopathies (FTLD is a representative of a whole class of neurological disorders). Like AD, there are no known treatments or cures for FTLD. AD and FTLD are two manifestations of a class of diseases known as tauopathies, due to the presence of toxic forms of tau.
Tau is a protein normally found in neurons. It functions as a stabilizer for microtubules, and has a role in the trafficking of materials from the cell body to the presynaptic terminal. In AD and FTLD, tau can become hyperphosphorylated, which causes it to form twisted fibrils called NFTs. An emerging area of research is to identify antibodies that target tau as a way to clear tau pathology and hopefully reduce synaptic and neuron loss (Boutajangout et al., 2011b). While these diseases have no known cure or treatment at present, immunotherapy is emerging as a promising approach for treatment. The studies presented here investigated a variety of antibodies directed against tau, and incorporated different timeframes and administration routes to identify the best candidate for future clinical investigation of tau immunotherapy.
The mouse model rTg4510, known for expressing cognitive-related tauopathy, was primarily used to evaluate tau antibody effectiveness prior to clinical consideration. Our investigations began by utilizing a more familiar mouse which was also reported to express tau pathology.
Our studies first examined intracranial injection of a variety of antibodies using a mouse model previously reported to demonstrate tau pathology, to identify short-term clearance of tau pathology and NFTs. Next, we examined a more robust tau-producing mouse line, to further identify a most effective antibody, as well as to examine the time course of effect, after administration. A longer-term administration, and different route of administration was tested using mini-osmotic pump implantation into the mice, which provided for 28-day continuous infusion. This approach was followed with administration of antibodies, systemically. Behavioral analysis, in addition to pathological testing, was incorporated into the longer-term administration studies.
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Pashmi, Ghazaleh. "Immunotherapy approach to combat nicotine addiction." Thesis, University of Bath, 2004. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419340.
Full textAbstract:
Smoking is now recognized as the single largest avoidable cause of premature death and disability in Britain and probably the greatest avoidable threat to public health worldwide. There are several therapies available to combat nicotine addiction ranging from psychological therapy to pharmacological interventions such as Nicotine Replacement Therapy. However, success rates for these therapies individually and mixture of therapies together, are still low and can be improved. A new strategy in helping quit rates is immunotherapy. This research project has focused on targeting cotinine, the major metabolite of nicotine, to produce a vaccine as a cessation method. The effect of cotinine on nicotine-evoked dopamine release was first examined using 96-well plate assay in chapter 2. Cotinine was shown to decrease nicotine - evoked dopamine release, probably by desensitising the nAChRs. a6p2*, a4p2 receptor subtypes were implicated, using competitive antagonists. Trans-4-thiol cotinine was produced as a viable derivative and conjugated to ovalbumin in the appendix and chapter 3. Vaccination of rats generated anti-cotinine antibodies, although mid-point titres were low. Improvements were made in chapter 4 which increased the mid-point antibody titres. The improvements included change of carrier molecule to Tenatus Toxoid, allowing for 15 derivative attachments per carrier molecule, and change of adjuvant. The best concentration of conjugate to be used in vaccination was determined to be 5 pg which produced specific antibodies towards cotinine. Blood nicotine and cotinine concentrations after chronic nicotine treatment showed vaccination resulted in the retention of cotinine in the blood, presumably reducing the concentration reaching the brain, in chapters 4 and 5. Similar results were also obtained after acute nicotine treatment in chapter 5. The effect of vaccination on nicotine - evoked dopamine release was studied in chapters 4 and 5; an increase in nicotine-evoked dopamine release was observed in vaccinated animals. This suggests the retention of cotinine in the blood and the consequent reduction of antagonism of the actions of nicotine by cotinine, allowed nicotine to have a larger effect. Nicotineinduced locomotor activity was not affected by vaccination, however future work is needed to give conclusive results. These results have provided preliminary proof of concept for this immunotherapy approach. Future in vivo experiments will elucidate the actions of this vaccine on addiction mechanisms and facilitate the development of this approach as a therapy to help people overcome nicotine addiction.
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Harley, Eric. "Modeling Cancer Cell Response to Immunotherapy." Scholarship @ Claremont, 2004. https://scholarship.claremont.edu/hmc_theses/164.
Full textAbstract:
Significant work has been done modeling cancerous tumor growth and response to therapy under certain simplifying assumptions, specifically, the assumption of spatial homogeneity. We have chosen a spatially heterogenous model for cancer cell growth using a hybrid Lattice-Gas Cellular Automata method. Cell mitosis, apoptosis, and necrosis are explicitly modeled along with the diffusion of nutrients and a necrotic signal. The model implementation is verified qualitatively and is modified to execute on a parallel computer.
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Bergeron, Anabel. "Improving Immunotherapy Using Vanadium-Based Compounds." Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/40099.
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Coletti, Roberta. "Mathematical modeling of prostate cancer immunotherapy." Doctoral thesis, Università degli studi di Trento, 2020. http://hdl.handle.net/11572/265805.
Full textAbstract:
Immunotherapy, by enhancing the endogenous anti-tumor immune responses, is showing promising results for the treatment of numerous cancers refractory to conventional therapies. However, its effectiveness for advanced castration-resistant prostate cancer remains unsatisfactory and new therapeutic strategies need to be developed. To this end, mathematical modeling provides a quantitative framework for testing in silico the efficacy of new treatments and combination therapies, as well as understanding unknown biological mechanisms. In this dissertation we present two mathematical models of prostate cancer immunotherapy defined as systems of ordinary differential equations.
The first work, introduced in Chapter 2, provides a mathematical model of prostate cancer immunotherapy which has been calibrated using data from pre-clinical experiments in mice. This model describes the evolution of prostate cancer, key components of the immune system, and seven treatments. Numerous combination therapies were evaluated considering both the degree of tumor inhibition and the predicted synergistic effects, integrated into a decision tree. Our simulations predicted cancer vaccine combined with immune checkpoint blockade as the most effective dual-drug combination immunotherapy for subjects treated with androgen-deprivation therapy that developed resistance. Overall, this model serves as a computational framework to support drug development, by generating hypotheses that can be tested experimentally in pre-clinical models.
The Chapter 3 is devoted to the description of a human prostate cancer mathematical model. The potential effect of immunotherapies on castration-resistant form has been analyzed. In particular, the model includes the dendritic vaccine sipuleucel-T, the only currently available immunotherapy option for advanced prostate cancer, and the ipilimumab, a drug targeting the cytotoxic T-lymphocyte antigen 4 , exposed on the CTLs membrane, currently under Phase II clinical trial. From a mathematical analysis of a simplified model, it seems likely that, under continuous administration of ipilimumab, the system lies in a bistable situation where both the no-tumor equilibrium and the high-tumor equilibrium are attractive. The schedule of periodic treatments could then determine the outcome, and mathematical models could help in deciding an optimal schedule.
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Coletti, Roberta. "Mathematical modeling of prostate cancer immunotherapy." Doctoral thesis, Università degli studi di Trento, 2020. http://hdl.handle.net/11572/265805.
Full textAbstract:
Immunotherapy, by enhancing the endogenous anti-tumor immune responses, is showing promising results for the treatment of numerous cancers refractory to conventional therapies. However, its effectiveness for advanced castration-resistant prostate cancer remains unsatisfactory and new therapeutic strategies need to be developed. To this end, mathematical modeling provides a quantitative framework for testing in silico the efficacy of new treatments and combination therapies, as well as understanding unknown biological mechanisms. In this dissertation we present two mathematical models of prostate cancer immunotherapy defined as systems of ordinary differential equations.
The first work, introduced in Chapter 2, provides a mathematical model of prostate cancer immunotherapy which has been calibrated using data from pre-clinical experiments in mice. This model describes the evolution of prostate cancer, key components of the immune system, and seven treatments. Numerous combination therapies were evaluated considering both the degree of tumor inhibition and the predicted synergistic effects, integrated into a decision tree. Our simulations predicted cancer vaccine combined with immune checkpoint blockade as the most effective dual-drug combination immunotherapy for subjects treated with androgen-deprivation therapy that developed resistance. Overall, this model serves as a computational framework to support drug development, by generating hypotheses that can be tested experimentally in pre-clinical models.
The Chapter 3 is devoted to the description of a human prostate cancer mathematical model. The potential effect of immunotherapies on castration-resistant form has been analyzed. In particular, the model includes the dendritic vaccine sipuleucel-T, the only currently available immunotherapy option for advanced prostate cancer, and the ipilimumab, a drug targeting the cytotoxic T-lymphocyte antigen 4 , exposed on the CTLs membrane, currently under Phase II clinical trial. From a mathematical analysis of a simplified model, it seems likely that, under continuous administration of ipilimumab, the system lies in a bistable situation where both the no-tumor equilibrium and the high-tumor equilibrium are attractive. The schedule of periodic treatments could then determine the outcome, and mathematical models could help in deciding an optimal schedule.
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Peng, Judy Chun-Ju. "Optimization of Dendritic cells for cancer immunotherapy /." [St. Lucia, Qld.], 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18443.pdf.
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Lute, Kenneth D. "Costimulation and tolerance in T cell immunotherapy." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1141850521.
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Safranek, Peter Michael. "Immunotherapy of colorectal cancer using bispecific antibodies." Thesis, University of Southampton, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418006.
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Zou, Li-Ping. "Immunoregulation and immunotherapy in experimental autoimmune neuritis /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3918-7/.
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Woods, David Michael. "Histone Deacetylases as Targets for Melanoma Immunotherapy." Scholar Commons, 2013. http://scholarcommons.usf.edu/etd/4856.
Full textAbstract:
Cancer represents the second leading cause of death in the United States. For many malignancies, currently available treatment options offer little long-lasting survival benefits to patients. However, recent studies have shown immunotherapeutic approaches to be an attractive strategy to cancer treatment. While many current immunotherapeutic strategies convey durable responses, such responses are only seen in a minority of patients. An increased understanding of the mechanisms governing tumor immunogenicity and the biology of immune responses is crucial to improving upon the efficacy of current and future cancer immunotherapies. Histone deacetylases (HDACs), enzymes classically associated with regulation of gene expression, have been therapeutic targets in various cancers for several years due to their involvement in cell growth. However, it has become increasingly clear that HDACs are intimately involved in regulating both the immunogenicity of tumor cells and immune response of leukocytes and lymphocytes. In order to expand upon this growing knowledge, the therapeutic efficacy of the pan-HDAC inhibitor LBH589 in the treatment of melanoma was studied. The results presented here demonstrate that LBH589 is a potent inhibitor of growth in a wide variety of melanomas through induction of cell cycle arrest and apoptosis. Additionally, LBH589 increases the immune visibility of melanoma cells by increasing expression of several immune associated cell surface markers (e.g. MHC I, MHC II, CD80, CD86) in addition to upregulating expression of melanoma differentiation antigens. Furthermore, LBH589 treatment of immune cells results in an enhanced pro-inflammatory phenotype of both APCs and T-cells. These combined effects result in better activation of T-cells and ultimately prolonged survival in LBH589 treated, melanoma-baring mice. To further the understanding of the role of individual HDACs in the T-cell response, the biology of the newest HDAC, HDAC11, was further assessed. To this end, it is shown that HDAC11 is differentially expressed in T-cell populations, and expression is rapidly decreased following activation. Utilizing an HDAC11 knockout (HDAC11KO) mouse strain, it is found that both CD4+ and CD8+ T-cells lacking HDAC11 have an enhanced type 1 effector function characterized by increased proliferation and secretion of IL-2, TNF and IFN-γ. Additionally, HDAC11KO CD8+ T-cells have increased expression of both granzyme B and perforin. HDAC11KO T-cells also demonstrate enhanced resistance to inhibition by Tregs and anergy formation. As a possible mechanism for the observed phenotype, it is also demonstrated that HDAC11KO T-cells produce elevated levels of the transcription factors Eomes and T-bet, both at the basal state and post-activation. In vivo, T-cells lacking HDAC11 have a more potent and robust ability to cause GvHD and mediate an enhanced anti-tumor response. Collectively, these results demonstrate that targeting of HDACs is a viable approach to cancer immunotherapy, and that targeting of specific HDACs may be an attractive strategy for optimizing immunotherapy efficacy while minimizing side effects.
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Siapati, Konstantina Elena. "Neuroblastoma immunotherapy using a novel vector system." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395647.
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Barnard, Amanda Louise. "A murine model for immunotherapy of melanoma." Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298460.
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Paredes, Moscosso Solange Rosa. "ROR1 as a target for cancer immunotherapy." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/10038730/.
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Receptor tyrosine-kinase like orphan receptor (ROR1) is a member of the tyrosine kinase family. Importantly, ROR1 is absent in healthy, critical tissue but overexpressed in various solid and haematological malignancies, including Chronic Lymphocytic Leukaemia (CLL). Moreover, recent studies suggest ROR1 is expressed on cancer stem cell-like cells (CSCs). The overriding aim of this study was therefore to combine the unique features of ROR1 with the exquisite specificity/therapeutic potential of monoclonal antibodies (MAbs) and/or their derivatives. To this end, our group generated a rat hybridoma library and screened >150 anti-ROR1+ clones. I then cloned 16 of our novel antibodies to human IgG1, kappa constant regions, of which 12 recognised ROR1 on different cell types. Based on functional/characterisation data, it was identified that clone SA1 exhibited significant CDC activity on primary CLL cells, whilst clone F was the only MAb able to bind the Frizzled domain of ROR1. Further investigation, however, revealed clone SA1 bound non-specifically to ROR1- cells. Therefore, my investigation focused instead on clone F, which was developed in parallel as a bispecific T-cell engager (BiTE) within our group. Having shown F BiTE elicited potent and specific cytotoxicity of ROR1+ cells on various solid cancer cell lines, including pancreatic cancer (PaCa), ROR1 BiTE was tested on PaCa cell line-derived CSCs using an in vitro tumoursphere model. Immunocytochemistry data confirmed specific elimination of cells expressing both CSC biomarkers and ROR1. As a whole, ROR1 MAb-based immunotherapy, particularly using BiTEs, seems to not only target ROR1+ cells present in the bulk of the tumour but, crucially, it also eliminates ROR1+ CSC subsets in PaCa. This approach represents a relevant and much needed addition to the current options for cancer treatment. Further preclinical and clinical studies will ultimately reveal the true therapeutic potential of ROR1 BiTEs alone and in combination.
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Tzeng, Alice. "Improving methods for cytokine immunotherapy of cancer." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/104233.
Full textAbstract:
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2016.Cataloged from PDF version of thesis.
Includes bibliographical references.
Cytokine therapy can activate potent antitumor responses, yet collateral toxicity often limits dosages. Although immunocytokines have been designed with the intent to localize cytokine activity, systemic dose-limiting side effects are not fully ameliorated by attempted tumor targeting. In the first part of this work, we used the B 1 6F 10 melanoma model to demonstrate that a nontoxic dose of IL-2 immunocytokine synergized with tumor-specific antibody to significantly enhance therapeutic outcomes compared to monotherapy with immunocytokine, concomitant with increased tumor saturation and intratumoral cytokine responses. Examination of cell subset biodistribution showed that the immunocytokine associated mainly with IL-2R-expressing innate immune cells, with more bound immunocytokine present in systemic organs than in the tumor microenvironment. More surprisingly, immunocytokine antigen specificity and Fc[gamma]R interactions did not appear necessary for therapeutic efficacy or biodistribution patterns, as immunocytokines with irrelevant specificity and/or inactive mutant Fc domains behaved similarly to tumor-specific immunocytokine. IL-2-IL-2R interactions, rather than antibody-antigen targeting, dictated immunocytokine localization; however, the lack of tumor targeting did not preclude successful antibody combination therapy. This study presents a safe, straightforward strategy for augmenting immunocytokine efficacy via supplementary antibody dosing and explores underappreciated factors that can subvert efforts to purposefully alter cytokine biodistribution. Numerous studies have identified cancer immunotherapy combinations that exhibit synergistic antitumor activity, but surprisingly, these studies rarely consider the effects of relative dose timing. In the second part of this work, using established syngeneic tumor models, we found that staggering IFN[alpha] administration after, rather than simultaneously with, serum-persistent IL-2 and tumor-specific antibody significantly increased long-term survival and generated immunological memory. Successful combination therapy required IFNa-induced activation of cross-presenting CD8[alpha]+ DCs following release of antigenic tumor debris by the IL-2-and-antibody-mediated immune response. Due to decreased phagocytic ability post-maturation, DCs activated too early captured much less antigen and could not effectively prime CD8+ T cells. Temporally programming DC activation to occur after tumoricidal activity enhanced tumor control by multiple combination immunotherapies that act through distinct mechanistic pathways, presenting a facile strategy for augmenting efficacy in the combinatorial treatment setting and highlighting dose schedule as an overlooked factor that can profoundly affect the success of multi-component immunotherapies.
by Alice Tzeng.
Ph. D.
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Howland, Shanshan W. "Yeast-based vaccine approaches to cancer immunotherapy." Thesis, Massachusetts Institute of Technology, 2008. http://hdl.handle.net/1721.1/45949.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2008.Includes bibliographical references.
Saccharomyces cerevisiae stimulates dendritic cells and represents a promising candidate for cancer immunotherapy development. Effective cross-presentation of antigen delivered to dendritic cells is necessary for successful induction of cellular immunity. Using a yeast vaccine model, we investigated the phagosome-to-cytosol pathway of cross-presentation. We demonstrate that the rate of antigen release from phagocytosed yeast directly affects cross-presentation efficiency, with an apparent time limit of about 25 min post-phagocytosis for antigen release to be productive. Antigen expressed on the yeast surface is cross-presented much more efficiently than antigen trapped in the yeast cytosol by the cell wall. The cross-presentation efficiency of yeast surface-displayed antigen can be increased by the insertion of linkers susceptible to cleavage in the early phagosome. Antigens indirectly attached to yeast through antibody fragments are less efficiently cross-presented when the antibody dissociation rate is extremely slow. Next, we present a yeast-based cancer vaccine approach that is independent of yeast's ability to express the chosen antigen, which is instead produced separately and conjugated to the yeast cell wall. The conjugation method is site-specific (based on the SNAP-tag) and designed to facilitate antigen release in the dendritic cell phagosome and subsequent translocation for cross-presentation.
(cont.) Phagosomal antigen release was further expedited through the insertion of the invariant chain ectodomain as a linker, which is rapidly cleaved by Cathepsin S. The dose of delivered antigen was increased in several ways: by using yeast strains with higher surface amine densities, by using yeast cell wall fragments instead of whole cells, and by conjugating multiple layers of antigen. The novel multi-layer conjugation scheme is site-specific and takes advantage of Sfp phosphopantetheinyl transferase, enabling the antigen dose to grow linearly. We show that whole yeast cells coated with one layer of the cancer-testis antigen NY-ESO-1 and yeast hulls bearing three layers were able to cross-prime naive CD8+ T cells in vitro, with the latter resulting in higher frequencies of antigen-specific cells after ten days. This cross-presentation-efficient antigen conjugation scheme is not limited to yeast and can readily be applied towards the development of other particulate vaccines.
by Shanshan W. Howland.
Ph.D.
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Gai, Shuning. "Engineering persistent interleukin-2 for cancer immunotherapy." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/76957.
Full textAbstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2012.Cataloged from PDF version of thesis.
Includes bibliographical references (p. 102-109).
Mobilizing the immune system to recognize and destroy tumor cells is a promising strategy for treating cancer. In contrast to standard therapeutic approaches such as surgery, radiation, and chemotherapy, immunotherapy offers the possibility of systemic yet tumor-specific cell killing as well as long-lasting cancer protection. A significant mode of tumor rejection is direct tumor cell killing by immune cells, such as cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. These cell types are stimulated to proliferate by the cytokine interleukin-2 (IL-2). Consequently, IL-2 has been actively pursued as an agent for immunotherapy, either alone or in combination with other therapeutic strategies. IL-2 is characterized by rapid systemic clearance, with a fast-phase serum half-life of 13 minutes and a slow-phase half-life of 85 minutes. We hypothesized that prolonging the persistence of IL-2 at the cell surface or extending its circulation lifetime would increase its immunostimulatory potency. Therefore, we evolved murine IL-2 to bind the alpha subunit of its receptor, known as IL-2Ra or CD25, with 500-fold higher affinity; tethered IL-2 to the surface of T cells via streptavidin sandwiches; and fused IL-2 to the antibody Fc fragment, designated Fc/ IL-2, which extended the slow-phase serum half-life by 15 hours. Compared to free IL-2, Fc/IL-2 fusions induced superior control of solid tumors in mice. Interestingly, combining Fc/IL-2 with an anti-tumor antibody led to potent suppression of tumor growth during treatment. Furthermore, combination therapy protected two of three mice from subsequent tumor re-challenge. Depletion of CTLs or NK cells completely or partially, respectively, abrogated treatment efficacy, suggesting these immune cell types contribute to the anti-tumor response. In the context of Fc fusion, increasing the affinity of IL-2 for CD25 did not further improve efficacy. Ablation of CD25 binding, however, significantly reduced efficacy and also increased treatment toxicity. Since we employed a mutant Fc with disrupted FcyR binding, and hence reduced effector function, and fused IL-2 to mutant Fc monovalently, the significant therapeutic benefit of Fc/IL-2 over free IL-2 likely results from the extension of IL-2 circulation lifetime. We hypothesize that long-circulating IL-2 would potently synergize with other anti-tumor antibodies for effective cancer immunotherapy.
by Shuning Gai.
Ph.D.
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Alisa, A. A. H. I. "Alpha-fetoprotein and immunotherapy for hepatocellular carcinoma." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1344163/.
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Background and Aims: Hepatocellular carcinoma (HCC) often presents at a late stage which limits the use of curative therapy. Hence the pressing need for increasing research into newer therapies such as immunotherapy. Alpha-Fetoprotein (AFP) is an oncofetal antigen elaborated in most HCCs and is a tumour rejection antigen in animal models for HCC making it a target for the development of T cell based immunotherapy. The effect of AFP on antitumour immune responses in patients with HCC has not been explored in depth. We aimed to study the effects of AFP on the immune system cells including dendritic cells (DCs). In man, naturally occurring anti-AFP CD8 T cell responses have been detected in patients with HCC. One vital step for the design of epitope-based therapeutic vaccines is the identification and characterization of T-cell epitopes on AFP. Several AFPderived peptides have been identified and T cells recognizing these epitopes have been studied in patients with HCC. However, the role of anti-AFP CD4+ T cell responses (Th1 cells or regulatory T cells) in HCC patients has not been studied. Also, our aim was to study the role of Th1 cells in HCC patients and investigate any possible association between the expansion of these cells with clinical features of the disease such as stage of disease, serum AFP levels and tumour invasiveness. Results and Conclusions: In our first study, the treatment of monocyte-derived DCs with AFP led to DC dysfunction as detected by the down-regulation of surface molecules (CD40 and CD86) and inhibition of their T cell-stimulatory capacity. In addition, AFP treatment induced apoptosis of DCs and reduced their ability to produce TNF-alpha and IL-12. Our ex vivo results showed that the ability of monocytes, isolated from patients with elevated levels of serum AFP (>1,000 ng/ml), to produce TNF-alpha was impaired. In the second study we identified an AFP-derived T cell epitope that was recognized by circulating CD4+ T cells from patients with HCC and normal or mildly elevated AFP level in the early stage of the disease. This response was absent in healthy donors and in patients with chronic liver disease, which suggested that this response had been previously expanded in vivo in response to the tumour. The induction or activation of regulatory T cells (T-regs) by tumours or pathogens may suppress protective immunity. In the third study, we demonstrated that AFP contained an epitope which activated the expansion of inducible TGF-beta producing T-regs. In our fourth study we revealed that CD4 T-cell response expanded in the early stages of disease (Child–Pugh A score), which is usually associated with low concentrations of serum AFP. Furthermore, CD8 T cell response was largely detected in HCC patients with a Child–Pugh B or C score. Necrosis of tumour cells can activate both innate and adaptive antitumor immunity. In a further study by our group, development of higher frequencies of AFP-specific CD4+ T cells after embolisation therapy was noted. Necrosis produced by Transarterial Chemoembolization (TACE) or Chemoembolization (TAE) unmasks tumour rejection Antigen-specific T cell responses. This represented a method of in situ immune response induction that could be combined with immunotherapy to increase the frequency of AFP-specific T cells with the aim of controlling tumour growth and improving survival. Also, two further HLA-DR-restricted AFP-derived CD4+ T cell epitopes were detected. From our studies thus far, we concluded that predictive factors for detecting an AFP-specific Th1 response in patients with HCC included a serum AFP of <1000 ng/ml, Okuda stage 1 and treatment with TACE/TAE.
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Perro, M. "Lentiviral TCR gene transfer for tumour immunotherapy." Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/134272/.
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The ability to manipulate the immune system to induce protection against tumour, is one of the most fascinating challenges in immunology. In this regard, TCR gene transfer is an attractive and powerful strategy to generate high numbers of tumour antigen-specific T cells for adoptive transfer treatment. This thesis describes the optimization of lentiviral vectors for TCR gene transfer in the absence of polyclonal activation of the transduced T cells, which may improve subsequent adoptive T cell therapy. The murinised and codon optimised chains of an HLA-A*0201-restricted TCR specific for Wilms` tumour antigen 1 were cloned in lentiviral vector constructs improved with a Leader sequence and the WPRE elements for redirecting T cells specificity. The effects of common gamma chain receptor cytokines IL-2, IL-7, IL-15 and IL-21 were investigated using WT1 TCR-transduced T cells for transduction efficiency, proliferative potential, phenotype and functional activity in response to cognate antigen. Although all cytokines tested allowed transduction, stimulations with IL-15 and IL-15 with IL-7 or with IL-21 promoted a higher efficiency. Expression analysis of CD28 and CD62L showed an important role of IL-21 in maintenance of a naïve phenotype. In addition, all cytokines promoted maintenance of “quality” of T cells as shown by co-expression of IL- 2, IFN-γ and TFN-α after specific stimulation. To further sustain the in vitro results, several in vivo models were tested. Consistently, using F5 transgenic mice recognizing the NP peptide presented on EL4-NP cell line, IL-15 with IL- 21 exposed CD8+ T cells were able to efficiently protect against tumour and to persist longer in tumour bearing mice compared to IL-2 treated T cells. Because previous reports demonstrated that efficient LN homing of T cell correlates with efficient tumour protection in vivo, an imaging approach to study the molecular signalling in vivo during T cell activation in the LN has been developed. In conclusion, in this thesis, it is demonstrated that lentiviral transduction of cytokine exposed T cell can improve gene therapy approach of adoptive therapy.
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Sydorchuk, Ruslan Ihorovych, Larysa Petrivna Sydorchuk, Oleh Yosipovych Khomko, Olexandr Matviyovuch Plehutsa, and Olexandr Oksentiyovuch Karliychuk. "The use of immunotherapy for abdominal sepsis." Thesis, Матерiали 97-ї пiдсумковоi' наукової конференцiї професорсько-викладацького персоналу вищого державного навчального закладу України «Буковинський державний медичний унiверситет» (Чернiвцi, 15, 17 ,22 лютого 2016 р.) - Чернiвцi: Медунiверситет, 2016, 2016. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/10452.
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Sydorchuk, Ryslan Ihorovuch, Larysa Petrivna Sydorchuk, Oleh Yosypovych Khomko, Oleksandr Matviyovych Plehutsa, and Oleksandr Oksentiyevych Karliychuk. "The use of immunotherapy for abdominal sepsis." Thesis, Матерiали 97-ї пiдсумковоi' наукової конференцiї професорсько-викладацького персоналу вищого державного навчального закладу України «Буковинський державний медичний унiверситет» (Чернiвцi, 15, 17 ,22 лютого 2016 р.) - Чернiвцi: Медунiверситет, 2016, 2016. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/10401.
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Zwaveling, Sander. "Immunotherapy of cancer through targeting of p53 /." [S.l. : s.n], 2003. http://catalogue.bnf.fr/ark:/12148/cb402204172.
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Stewart, Trina Jane. "Adoptive immunotherapy studies of HPV16E7-expressing tumours /." St. Lucia, Qld, 2002. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16089.pdf.
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Abozeid, Mohamed. "Imaging and Radio-immunotherapy of pancreatic cancer." Doctoral thesis, Università degli studi di Padova, 2018. http://hdl.handle.net/11577/3422678.
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Background
The aims of this study are imaging and Radio-immunotherapy (RIT) of pancreatic cancer through the development of new target-specific radiopharmaceuticals based on mAb directed to prostate stem cell antigen (PSCA) and Mesothelin antigen, which are heavily overexpressed in this tumor histotype.
Methods
Flow cytometry studies were carried out in order to confirm the ability of both anti-APSCA (APSCA) and anti-mesothelin (AM) mAbs to recognize the specific antigen receptors PSCA and mesothelin on the surface of the malignant cells. Two tumor cell lines were used, the human pancreatic adenocarcinoma T3M4 cell transduced or not to express PSCA receptors (T3M4-PSCA) and the embryonic human kidney 293-cell transduced or not to express mesothelin receptors (293-Meso).
Cytometry studies were done to identify the expression of PSCA and Mesothelin antigen on the cell surface. First, both mAbs conjugated to Alexa 680 using the SAIVI rapid antibody labelling kit, the labelled products was purified and the labelling degree and protein concentration were determined by absorbance. Then, 3x105 cells were stained with 1 µg of Alexa 680-APSCA or Alexa 680-AM mAbs to be analysed using a FACS Calibur flow cytometry.
Optical imaging studies were performed in mice to confirm the ability of both mAbs to identify specifically the antigens in vivo.
Direct labelling of APSCA and AM mAbs was performed by reduction of mAb disulphide bridges with 2-mercaptoehanol (2-ME). Reduced mAbs were radiolabeled by the addition of eluted 99mTc-pertechnetate to mAb, followed by the reducing agent SnCl2. The preparation was incubated at room temperature and gently mixed. Radiochemical purity (RCP) analyses were performed using radio-HPLC and stability was tested after dilution in different solutions at different ratios.
Conjugations of DOTA were done by incubation of p-SCN-Bz-DOTA to APSCA and AM mAbs, then characterization studies of DOTA conjugates were done using size exclusion HPLC. Conjugated mAbs were indirectly radiolabelled with Lutetium-177 177(Lu), incubated at 37oC and labelling efficiency (LE) was evaluated. Stability against dilution and transchelation were also assessed at different time points by size exclusion HPLC and ITLC-SG.
Results and conclusions
AM and APSCA mAbs that efficiently detected pancreatic cancer cells in vitro and in vivo were successfully labeled using direct and indirect methods with 99mTc and 177Lu, respectively. All the resulting compounds were prepared by rapid simple methods and demonstrated high RCP, high in vitro stability and high in vitro binding specificity. Therefore, our results are highly encouraging and open additional opportunities for further in vivo studies to assess such mAbs as novel imaging diagnostic and effective therapeutic tools in pancreatic cancer.Gli obiettivi di questo studio sono l'imaging e la radioimmunoterapia (RIT) del cancro del pancreas attraverso lo sviluppo di nuovi radiofarmaci target-specifici basati su mAb diretti all'antigene della prostata staminale prostatica (PSCA) e all'antigene della mesotelina, che sono fortemente sovraespressi in questo istotipo tumorale . Gli mAb AM e APSCA che hanno rilevato in modo efficiente le cellule di cancro al pancreas in vitro e in vivo sono stati etichettati con successo usando metodi diretti e indiretti con 99mTc e 177Lu, rispettivamente. Tutti i composti risultanti sono stati preparati con metodi semplici rapidi e hanno dimostrato un alto RCP, elevata stabilità in vitro ed elevata specificità di legame in vitro. Pertanto, i nostri risultati sono altamente incoraggianti e aprono ulteriori opportunità per ulteriori studi in vivo per valutare tali mAb come nuovi strumenti diagnostici per immagini e strumenti terapeutici efficaci nel cancro del pancreas.