No description available.

Cancer affects a wide range of organs and tissues within the body and epidemiologically is forecasted to affect almost half of the world's population. As an industry, cancer therapeutics represent a booming field. Standard treatment options, however, still heavily rely upon chemotherapeutics developed over fifty years ago. The past decade has seen a huge proliferation of different types of cancer drugs. Recently, an entirely new class of drugs has been unveiled and holds promising results of preventing further relapse incidents. Immunotherapeutics come in many varieties and currently several strategies are under intense investigation. Because these drugs harness the body's own immune system to specifically attack tumor cells, these drugs hold an advantage to current therapeutic options in that they induce notably less severe side effects, facilitating patients' abilities to maintain quality of life. In addition, these drugs potentially hold the promise to cure certain types of cancer, as the body's memory T cells will prevent relapse of the same tumor type. This review will focus on dendritic cell-based therapies, which attempt to program these antigen-presenting cell types to prime T cell responses, checkpoint blockade drugs that inhibit immunosuppression, and neoadjuvants that aim to render the surrounding tumor microenvironment more susceptible for immune attack. In addition, some documented and projected downsides to immunotherapeutics will be discussed, as well as the need to combine multiple modalities in order to create an effective and personalized treatment regimen for cancer patients.

Thesis (M.D.)—Boston University

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Cancer therapies have evolved continuously, with the newest class being immunotherapies targeting the PD‐L1/PD‐1 pathway. This pathway is often overexpressed in malignancies, which allow the aberrant cells to evade the body’s natural immune response that would normally eliminate them. The novel therapies currently being investigated are monoclonal antibodies that target either the PD‐L1 on the tumor cell or the PD‐1 on the lymphocyte. Considering there are significant toxicities with these therapies, namely gastrointestinal and endocrine adverse effects, a predictive tool that could allow physicians which patients are likely to respond to these immunotherapies could spare patients unnecessary therapy and potential economic harm. Since repetitive imaging of patients with cancer is necessary to monitor treatment response, advanced imaging analysis techniques on standard of care images, such as CT scans may provide insights into tumor patterns that could help to predict treatment response. Quantitative texture analysis (QTA) of computed tomography scans has been used in various settings to examine tissue heterogeneity as a predictive biomarker of response; we hypothesized that QTA may have potential value in predicting tumor response to immunotherapy. We performed a QTA on standard of care CT scans from patients to determine if a unique textural imaging signature could be identified that would serve as a predictive biomarker for response to PD‐L1/PD‐1 therapies in subjects with solid tumor malignancies in the lungs, liver, and lymph nodes. This study examined the diagnostic standard of care CT scans of the chest, abdomen, and pelvis (CT CAP) at baseline and follow‐up, which were acquired as part of routine clinical care for tumor staging and treatment response in 20 subjects whose personal health care information was removed prior to analysis. Regions of interest (ROI) were drawn around all identifiable tumor lesions on baseline CT scans provided that tumors were of reasonable size (>10 mm in diameter) and conspicuity. CT texture analysis was performed on these lesions to obtain a histogram readout of tumor texture based upon tissue densities on a per pixel bases. The output values from the QTA platform provided an estimate of tumor signal properties as expressed as the mean pixel density, standard deviation, entropy, kurtosis, skewness, and mean positive pixel values. Each subject was designated as achieving either a RECIST based treatment response or not. Statistical modeling was then conducted using regression techniques. There was no identifiable signature when examining all of the lesions together, but there were statistically significant correlations noted between QTA and RECIST responses for lung‐based lesions. The QTA derived mean pixel density parameter was a major component of separating out responders from non‐response. Of the 14 lung lesions (8 responder vs. 6 nonresponder) there was a significant difference in the mean density with a threshold cutoff of 11.91 (p < 0.0001). A Mann‐Whitney U‐test was performed on the total data set yielding a Z statistic of 2.6 (p=0.0092). Despite the relatively small number of patients in this initial study, there were promising findings regarding the mean density of lesions, suggesting that texture analysis can be used to predict if patients respond to PD‐L1/PD‐1 inhibitors. Further investigation is warranted in a larger population that can be differentiated by tumor type to validate these results.

No description available.

Typescript (photocopy) / ix, 309 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--Dept. of Obstetrics and Gynaecology, University of Adelaide, 1981

Copies of author's previously published article inserted onto back cover. Bibliography: leaves 164-187. Confirms the value of DHBV infection in ducks as a model to evaluate the protective and therapeutic efficacy of DNA vaccines against hepadnavirus infection. The possibility that this model could be explored further to evaluate various combinations of antigens and cytokines 'cocktail' DNA vaccines that elicit the most effective humoral and effective CMI responses for prevention and treatment of HBV infection is discussed.

For the first time, two distinct, well-characterized water-soluble chemotherapeutic-C60 conjugates have been constructed for targeted drug delivery of paclitaxel to cancer cells. In vitro work was carried out in two stages to determine IC50 values of the conjugates. Primarily, work was carried out on A375m melanoma, T-24 bladder carcinoma, and Hep 3B hepatocellular carcinoma cell lines. In these studies, it was revealed that although the first compound, a paclitaxel-2’-succinate-C60 derivative, experienced a dramatic loss of cytotoxicity in comparison to paclitaxel, the second derivative, utilizing a poly(ethylene glycol) linker, demonstrated over 10× better cytotoxicity than paclitaxel itself. Additional in vitro studies were carried out for the purpose of creating a chemotherapeutic-fullerene-monoclonal antibody immunoconjugate for targeted drug delivery. Building on our previous work, supermolecular forces, instead of covalent chemical bonding were used to associate antibodies with the paclitaxel-2’-succinate-C60 derivative to construct an immunoconjugate. While cytotoxicity was measurable, no discernible advantage was seen by the targeted C60-(ZME-018) immunoconjugate over a MuIgG control, thus leaving room for further refinement of the approach for targeted cancer therapy. In vivo work, using the potent paclitaxel-poly(ethylene glycol)-C60 derivative in a murine model, demonstrated success by producing a similar capacity for tumor-reduction compared to the FDA-approved drug Abraxane®, without the associated weight-loss in animals seen for Abraxane. A major contribution of this work is the progress made toward development of Fullerene Immunotherapy (FIT) and the potential translation of FIT into the clinic. Having demonstrated the potent, improved cytotoxicity of a paclitaxel-C60 conjugate, the next step in the development of FIT is the successful construction of a therapeutic fullerene-antibody immunoconjugate. The results documented in this work have now shifted the onus of FIT from a theoretical concept to a realistic goal awaiting final developmental refinement.

Prostate cancer is a leading cause of cancer deaths in North American men. Current treatments are often not curative, particularly in cases of advanced metastatic disease. Immunotherapy is a promising approach to treating cancer as it harnesses the immune system’s ability to mount potent responses against tumor-associated antigens (TAAs). Dendritic cells (DCs) play a central role in mediating antigen-specific immunity and have been recently used with some success in clinical trials. The difficulties associated with obtaining sufficient quantities of DCs from cancer patients provided the rationale for developing low-dose DC-based immunotherapy approaches in my thesis project. DCs were genetically engineered using a lentiviral vector (LV) to express erbB2tr, a kinase-deficient version of erbB2. The human form of erbB2, HER2/neu, is overexpressed in 20% of primary prostate tumors and 80% of their metastases, making this TAA an attractive target. Using this LV system, efficient transgene delivery into DCs was achieved without compromising DC function or phenotype. Administering low prime and boost doses (2x10^5 or 2x10^3) of LV-transduced DCs to mice yielded potent and long-term anti-tumor responses against murine prostate tumors engineered to overexpress erbB2tr. The 2x10^5 DC dose yielded complete tumor protection and was associated with humoral and cellular responses. The 2x10^3 dose also offered complete protection in some mice, suggesting that we had reached a lower threshold DC dose. This novel finding prompted us to determine if co-transducing DCs with an additional LV carrying the cDNA for an immunomodulatory factor could augment the efficacy of our low-dose strategy. We chose to test both the DC survival-enhancing RANKL protein and DC function-enhancing IL-12 in combination with erbB2tr. Although DCs co-transduced with the LV/RANKL and LV/erbB2tr did not appear to offer enhanced anti-tumor benefits in a prophylactic setting, co-transduction with LV/IL-12 and LV/erbB2tr did. The incorporation of IL-12 into the low-dose immunization strategy led to robust long-term tumor protection and relatively high levels of Th1 immunity. This is the first demonstration of the efficacy of low-dose DC-mediated immunotherapy using lentiviral vectors as gene transfer tools. These studies establish a platform for DC-mediated therapies that can be realistically translated to the clinic.

Prostate cancer is a leading cause of cancer deaths in North American men. Current treatments are often not curative, particularly in cases of advanced metastatic disease. Immunotherapy is a promising approach to treating cancer as it harnesses the immune system’s ability to mount potent responses against tumor-associated antigens (TAAs). Dendritic cells (DCs) play a central role in mediating antigen-specific immunity and have been recently used with some success in clinical trials. The difficulties associated with obtaining sufficient quantities of DCs from cancer patients provided the rationale for developing low-dose DC-based immunotherapy approaches in my thesis project. DCs were genetically engineered using a lentiviral vector (LV) to express erbB2tr, a kinase-deficient version of erbB2. The human form of erbB2, HER2/neu, is overexpressed in 20% of primary prostate tumors and 80% of their metastases, making this TAA an attractive target. Using this LV system, efficient transgene delivery into DCs was achieved without compromising DC function or phenotype. Administering low prime and boost doses (2x10^5 or 2x10^3) of LV-transduced DCs to mice yielded potent and long-term anti-tumor responses against murine prostate tumors engineered to overexpress erbB2tr. The 2x10^5 DC dose yielded complete tumor protection and was associated with humoral and cellular responses. The 2x10^3 dose also offered complete protection in some mice, suggesting that we had reached a lower threshold DC dose. This novel finding prompted us to determine if co-transducing DCs with an additional LV carrying the cDNA for an immunomodulatory factor could augment the efficacy of our low-dose strategy. We chose to test both the DC survival-enhancing RANKL protein and DC function-enhancing IL-12 in combination with erbB2tr. Although DCs co-transduced with the LV/RANKL and LV/erbB2tr did not appear to offer enhanced anti-tumor benefits in a prophylactic setting, co-transduction with LV/IL-12 and LV/erbB2tr did. The incorporation of IL-12 into the low-dose immunization strategy led to robust long-term tumor protection and relatively high levels of Th1 immunity. This is the first demonstration of the efficacy of low-dose DC-mediated immunotherapy using lentiviral vectors as gene transfer tools. These studies establish a platform for DC-mediated therapies that can be realistically translated to the clinic.