Download or read book Tumor Immunotherapy in the RM 1 Mouse Model of Prostate Cancer written by Julieanne Francine Grant and published by . This book was released on 2007 with total page 284 pages. Available in PDF, EPUB and Kindle. Book excerpt: Prostate cancer is the most frequently diagnosed noncutaneous cancer among men and a leading cause of cancer deaths. No curative treatment exists for hormone resistant prostate cancer, but immunotherapy has the potential to prevent disease recurrences and to destroy metastases. We investigated the efficacy of immunotherapy in the RM-1 model of prostate cancer. RM-1 cells are aggressive, non-immunogenic mouse prostate cancer cells that express very little MHC I, similar to many human prostate cancers. Our goal was to develop a whole cell tumor vaccine that would generate a protective T cell-dependent antitumor response.
Download or read book Prostate Cancer Immunotherapy Development in Prostate Specific Antigen Transgenic Mice written by and published by . This book was released on 1999 with total page 16 pages. Available in PDF, EPUB and Kindle. Book excerpt: Our research is focused towards the development of an immunotherapy for prostate cancer that specifically targets the expressed prostate specific antigen (PSA) of prostate tumor cells. With over forty thousand deaths a year and the near lack of curative treatments, an effective therapy would greatly benefit society. Our research to date has suggested that PSA can serve as a tumor rejection marker in our PSA transgenic mice whose prostates express human PSA. Vaccination with a tumor cell that expresses PSA elicited a specific anti-PSA response that prevented the outgrowth of a tumor challenge of PSA expressing cells. After indicating the pertinence of PSA as a target of an immunotherapy, we attempted to identify PSA derived peptides that are immunogenic in the HLA-A0̂20l haplotype. Of nine PSA peptides selected for our study based on binding studies, two have proven to be immunogenic in the HLA- A0̂2O1/Dd transgenic mouse model after vaccination of peptide pulsed dendritic cells. These results indicate that not only can we use PSA as a plausible rejection marker but we can also elicit a CTL response directed against the human PSA peptides in a HLA-A0̂20l/Dd transgenic mouse. These results allow us to experiment with our vaccination strategies for the development of an efficacious anti-prostate cancer immunotherapy.
Download or read book Targeting a Self tumor Antigen Expressed in the Prostate for Adoptive T Cell Immunotherapy of Prostate Cancer written by Cassie K. Chou and published by . This book was released on 2012 with total page 65 pages. Available in PDF, EPUB and Kindle. Book excerpt: Adoptive T cell therapy (ACT) for the treatment of established cancers is actively being pursued in clinical trials. However, poor in vivo persistence and maintenance of anti-tumor activity of transferred tumor-specific T cells remain major problems. Most identified tumor antigens are self-proteins, therefore T cells bearing high avidity TCRs for tumor antigens are often deleted in the thymus and any self/tumor-reactive T cells in the periphery are often eliminated or rendered dysfunction by peripheral tolerance mechanisms. The tumor microenvironment poses additional immunosuppressive obstacles, such as the expression of immunosuppressive cytokines and inhibitory ligands. Transforming growth factor beta (TGF[beta]) is a potent immunosuppressive cytokine that is required to prevent autoimmunity and is often present at high levels within tumor microenvironments. Programmed death ligand 1 (PD-L1) is an inhibitory ligand that is expressed by many cancers and it's receptor, PD-1, is expressed by many dysfunctional tumor-infiltrating T cells. One advantage of ACT is the ability to genetically engineer T cells to improve function, such as by transducing high affinity tumor-specific TCRs or disrupting inhibitory signaling pathways. In these studies, we used transgenic mouse models to (1) characterize prostate-specific T cell responses to the normal prostate and (2) evaluate the effects of abrogation of TGF[beta] and/or PD-1 signaling in self/tumor specific CD8 T cells for use in ACT of prostate cancer. First, we found that prostate-specific CD8 T cells were subjected to both central and peripheral deletion. Using an adoptive transfer model, we found that in vivo immunization and/or pre-activation of prostate-specific CD8 T cells resulted in prostate infiltration but no subsequent prostate damage. Second, we found that abrogation of TGF[beta] signaling increased persistence and augmented anti-tumor activity of self/tumor specific CD8 T cells in a murine model of autochthonous prostate cancer. However, over time, prostate infiltrating T cells became dysfunctional and expressed high levels of PD-1. Moreover, blockade of PD-1 signaling did not rescue or further sustain the function of these cells. These findings reveal that when targeting a tumor antigen that is also expressed as a self-protein, substantive obstacles in addition to TGF[beta] and PD-1 are operative within the tumor microenvironment.
Download or read book Targeting Radiation Therapy for Developing Dendritic Cell Based Immunotherapy of Metastatic Prostate Cancer written by and published by . This book was released on 2006 with total page 72 pages. Available in PDF, EPUB and Kindle. Book excerpt: In this proposal the effectiveness of developing a novel immunotherapeutic strategy following Radiotherapy for prostate cancer has been explored. The hypothesis was tested using a murine prostate cancer model, RM-1. The study showed that irradiation induces apoptosis and the irradiated tumor cells were able to activate dendritic cells and stimulate tumor specific immune response in vitro. In vivo immunization of animals with activated DCs was able to increase their survival against subsequent challenge with tumor cells. Treatment with CCL-21 following DC expansion by FL+IL-12 in animals bearing irradiated tumor, significantly increased their survival time when they were challenged with tumor cells. This regimen also generated a tumor specific immune response as evidenced by in vitro studies. Similar protection was observed when CD40L was used instead of CCL-21 following treatment with FL+IL-12. The study further showed that the administration of adenovirus (Ad-CCL-21) to prostate tumor bearing animals significantly increased their survival time. Collectively, our study provides anovel approach to treat advanced prostate cancer patients following radiotherapy. Aprotocol for treating prostate cancer patients undergoing radiotherapy could be developed immediately based on these findings.
Download or read book A Mouse Model for Prostate Cancer written by and published by . This book was released on 2001 with total page 26 pages. Available in PDF, EPUB and Kindle. Book excerpt: Mouse models of carcinogenesis have provided significant insights into the molecular mechanisms of tumor suppressor gene function. Our goal is to develop mouse models that recapitulate early stages of prostate carcinoma. Using such models we have demonstrated that the Nkx3.1 homeobox gene represents a prostate-specific tumor suppressor that undergoes epigenetic inactivation through loss of protein expression. Loss-of-function of Nkx3.1 in mice results in histopathological defects that resembles prostate cancer initiation in humans, and cooperates with loss-of-function of the Pten tumor suppressor gene in cancer progression. Furthermore, our findings suggest that the molecular mechanisms that mediate this cooperativity include the synergistic activation of Akt (protein kinase B), a key modulator of cell growth and survival. We propose that interactions between tissue-specific regulators such as Nkx3.1 and broad-spectrum tumor suppressors such as Pten underlie the distinct phenotypes of different cancers.
Download or read book Molecular Biology of Prostate Cancer written by Manfred Wirth and published by Walter de Gruyter. This book was released on 2013-05-22 with total page 220 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Combining Radiotherapy and Immunotherapy to Target Surviving in Prostate Cancer written by and published by . This book was released on 2008 with total page 12 pages. Available in PDF, EPUB and Kindle. Book excerpt: Here, we propose to harness the immune system by immunotherapy (IT) alongside conventional radiotherapy (RT) to improve the treatment of men with advanced or recurrent prostate cancer. The overall aim is to determine whether local irradiation of prostate tumors in a preclinical and clinical setting leads to measurable tumor-specific immune responses and whether tumor vaccination can boost these immune responses possibly leading to better tumor control. Survivin is our tumor antigen of choice because it seems superior to other prostate tumor antigens. We generated stable mouse prostate cancer cell lines (TRAMP C1 and TRAMP C2) that express human HLA-A2.1 and we were able to confirm that these cells express survivin. These are two important steps as this will allow us to examine the responses to human surviving epitopes that are clinically relevant within a transgenic humanized mouse model. Enumeration of circulating survivin-specific CD8+ T lymphocytes in prostate cancer patients using tetramers indicated that many patients have higher than normal numbers of these T cells and that they are increased further upon completion of radiation treatment. Whether or not this is due to increase in antigenic peptide liberation and whether this will translate to tumor regression we don't know. What is clear is that RT does not induce immune tolerance to surviving making IT approaches feasible in combination with RT.
Download or read book Combination Targeted Radionuclide Therapy and Immunotherapy for Prostate Cancer written by Hemanth Kumar Potluri and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: New treatments are needed for metastatic prostate cancer. While patients initially respond to therapies that block the androgen receptor signaling which is required for prostate cancer growth, nearly all patients ultimately develop resistance to androgen deprivation therapy. Immune checkpoint blockade has been highly successful in treating many cancer types which have proved resistant to other lines of therapy, but these treatments have not been successful as monotherapies for prostate cancer. In contrast, the role of radiation therapy for treating prostate cancer has continued to expand. In addition to the long history of treating localized disease with external beam radiation therapy (EBRT), systemic radiation treatments that are able to deliver therapeutic doses to all sites of metastatic disease with relative sparing of healthy tissues have recently been approved. This systemic radiation modality is called targeted radionuclide therapy (TRT). It has been shown that EBRT is capable of sensitizing poorly immunogenic tumors to respond to immunotherapy through several activating effects on immune populations within the tumor. However, it is unknown whether TRT agents, which are more appropriate for widely metastatic disease, can elicit similar effects on the prostate tumor microenvironment and enhance the efficacy of immunotherapies. In particular, we focused on characterizing NM600, an alkylphosphocholine TRT agent which is taken up by several tumor types, including prostate cancer, and can be radiolabeled with multiple different radiometals. The overarching hypothesis of this work is that TRT, delivered via NM600, can remodel the prostate tumor microenvironment, rendering it susceptible to treatment with immunotherapy. We first evaluated the effects of 90Y-labeled NM600 alone on mouse prostate tumor allograft models. We found that 90Y-NM600 elicited a dose-dependent anti-tumor response but did not cause tumor regression even at the highest tolerated doses. Within 90Y-NM600-treated tumors, we observed an initial infiltration of activated, effector memory CD8+ T cells, but observed high PD-1 and PD-L1 expression over time. Based on these data, we investigated the effects of 90Y-NM600 together with PD-1 blockade. We found that this combination did not significantly improve anti-tumor efficacy due to the activating effects of PD-1 blockade on regulatory T cells. Next, we evaluated 90Y-NM600 in combination with tumor-specific vaccination. Specifically, we used a DNA vaccine encoding the ligand-binding domain of the androgen receptor which our lab has shown to elicit antigen-specific CD8+ T cell responses in both rodent models and in humans. We hypothesized that since we found that TRT could increase CD8+ T cell infiltration and promote an effector memory CD8+ T cell response, treatment with this vaccine would favor antigen-specific CD8+ T cell infiltration into the tumor following TRT administration. We found that the combination of single treatment TRT at the highest tolerated dose and vaccine did not improve anti-tumor efficacy despite a further initial increase in effector memory CD8+ T cells in the tumors of combination treated animals. However, two doses of TRT given three weeks apart in combination with vaccine did appear to improve anti-tumor efficacy possibly through decreasing PD-1 and PD-L1 signaling. We also observed that while 6 Gy of TRT and 6 Gy of EBRT were equally ineffective at improving anti-tumor response in combination with vaccine, increasing the dose of EBRT to 12 Gy did result in an additive anti-tumor response. Finally, we compared the effects of NM600 labeled with different radioisotopes, specifically the beta emitter 177Lu and the alpha emitter 225Ac, on our prostate tumor models. We found that 225Ac-NM600 treatment elicited a stronger anti-tumor effect than 177Lu-NM600. 225Ac-NM600 treatment also resulted in a bias towards activated, memory CD8+ T cells with sustained depletion of Tregs within the tumor. This suggests that 225Ac-NM600 may be the superior choice of radioisotope for combination with immunotherapy. Overall, these data demonstrate that the efficacy of TRT and immunotherapy combinations appear to be heavily dependent on the dose, fractionation, and type of radiation used, as well as specific effects of the chosen immunotherapy on cell types whose presence are promoted by the radiation. Further investigation into radiation and immunotherapy combinations are warranted due to the highly translatable nature of these findings.
Download or read book Immunotherapy of Prostate Cancer by a Combination of Treatments Aiming at Activation of OX40 and Intratumoral Production of IL 12 written by Fahimeh Aeineh Negin and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Prostate cancer (PCa) is characterized by an immunosuppressive tumor microenvironment that inhibits antitumor immunity. Treatment with immunomodulators, such as cytokines (e.g., IL-12), could modify the immune response. However, systemic administration of immunomodulators can cause toxicities. To avoid these toxicities, the immunomodulators could be produced locally in the tumor using an adenoviral vector able to ensure PCa-specific expression of the transgene. Our laboratory previously constructed such an adenovirus encoding the murine IL-12 (mIL-12) under the control of the PCa-specific promoter PCA3 and an amplification system called TSTA. This adenovirus, named Adv-PCA3-TSTA-mIL-12, was shown to reduce the growth of TRAMP-C2 prostate tumor in C57BL/6 mice. Here, we aimed to test a possible synergistic effect of the activation of OX40 to improve the response observed with Adv-PCA3-TSTA-mIL-12. The murine OX40 (mOX40), along with its ligand (mOX40L), are immune checkpoints that belong to the Tumor Necrosis Factor superfamily. To achieve this goal, we proposed two approaches. In the first, we aimed to produce an Adv-PCA3-TSTA expressing mouse OX40L in order to use it in combination with Adv-PCA3-TSTA-mIL-12. The Adv-PCA3-TSTA-mOX40L was constructed, but its capacity to induce mOX40L expression in TRAMP-C2 cells has not been confirmed yet. In the second, agonistic anti-mOX40 monoclonal antibody (mAb) would be administered in combination with Adv-PCA3-TSTA-mIL-12. To test this approach, TRAMP-C2 cells were implanted in mice and tumors were treated by injections of Adv-PCA3-TSTA-mIL-12 alone or in combination with injections of anti-mOX40 or anti-mPD-1 (as comparator) mAbs. Results showed no statistically significant synergistic effects of the addition of treatment with anti-mOX40 to Adv-PCA3-TSTA-mIL-12. The immune cells infiltrating tumors showed few significant changes, except for a decrease in CD8++D-1+ cells in tumors treated with anti-mOX40 or anti-mPD-1 mAbs. The combination of OX40 stimulation with Adv-PCA3-TSTA-IL-12 appears to have no synergistic effect. We conclude by suggesting that more effective combinations should be looked for.
Download or read book Proto Oncogene PML and Tumor Evasion in Prostate Cancer written by and published by . This book was released on 2000 with total page 122 pages. Available in PDF, EPUB and Kindle. Book excerpt: The peptides presented by class I human leukocyte antigen (HLA) are the primary targets on tumor cells for immune recognition by host cytotoxic T lymphocytes (CTL). Tumors can therefore avoid CTL recognition by down-regulation of cell surface HLA. However, the molecular mechanism of HLA down-regulation and its significance in progression of prostate carcinoma have not been determined. We have proposed to identify the antigen presentation defects in prostate cancer, to examine the role of proto-oncogene PML in HLA class I down regulation in prostate cancer, and to study the immune regulation in experimental transgenic murine prostate cancer (TRAMP) models. In the past funding period, we have performed immunohistochemical study to show the concordant proto-oncogene PML and HLA class I antigen down-regulation in surgically removed prostate cancer lesions We have examined the proto-oncogene PML isoform expression and antigen presentation gene expression in prostate cancer cell lines. Most importantly, we made the important discovery that thymic deletion is the major mechanism of T cell immune tolerance in TRAMP mouse model. We believe that these works will open new revenues for prostate cancer immunotherapy.
Download or read book Tumor Suppressor Genes in the Pathogenesis of Prostate Cancer written by Suzana Sturlini Couto and published by . This book was released on 2008 with total page 344 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Development of Immunotherapy Against Prostate Cancer Using Lentivirally transduced Dendritic Cells Expressing Murine ErbB2 as a Model Tumor associated Antigen written by Miriam Esmat Mossoba and published by . This book was released on 2008 with total page 314 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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 (2x105 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 2x105 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, ii 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.
Download or read book Virology Methods Manual written by Hillar O. Kangro and published by Elsevier. This book was released on 1996-04-16 with total page 385 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Virology Methods Manual is a comprehensive source of methods for the study, manipulation, and detection of viruses. Edited by Brian Mahy and Hillar Kangro, this work describes the most up-to-date, definitive techniques, provided by experts in each area, and presented with easy-to-use, step-by-step protocols. This new manual will satisfy the needs of virologists and all those working with viruses who need a practical guide to methods that work! - Provides up-to-date techniques by experts worldwide - Presents common, step-by-step protocols in an attractive, easy-to-use fashion - Contains useful appendices including virus taxonomy, metabolic inhibitors, and Bio-safety in the virology laboratory
Download or read book Journal of the National Cancer Institute written by and published by . This book was released on 2001 with total page 690 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Formulated Delivery of Enzyme Prodrug and Cytokine Gene Therapy to Promote Immune Reduction of Treated and Remote Tumors in Mouse Models of Prostate Cancer written by and published by . This book was released on 2005 with total page 99 pages. Available in PDF, EPUB and Kindle. Book excerpt: Prostate cancer is the second highest cause of cancer death in men in Western society. Early disease is treatable by surgery or radiation, but once late stage disease becomes refractory to hormone removal, patient care is limited to pain management. New treatments are needed. We use gene therapy, alone and in combination with hormones called cytokines that stimulate the immune system. The concept is that delivering a cell-killing agent to an accessible tumor, coupled with help from the immune system can promote tumor reduction both at the treatment site and at remote locations. In this therapy, a gene (a fusion of cytosine deaminase and uracil phosphoribosyltransferase (CD/UPRT)) is delivered to a cancer cell by a virus, or expressed by molecular engineering, so that harmless bacterial proteins are made. When followed by a pro-drug, 5 fluorocytosine (5FC), cancer cells that make CD/UPRT convert SF0 to a toxin that kills the original and neighbouring cells. This system works in slow growing tumors like prostate cancer. Killing the tumor cells attracts immune cells. We are identifying these and then delivering cytokine genes that attract more immune cells into the tumors. We will deliver the cytokine gene alone or with the suicide gene because in other studies, combination therapy works better.
Download or read book Developing a Hoxb13 based Mouse Model of Lethal Metastatic Prostate Cancer written by Nicole Briceno and published by . This book was released on 2015 with total page 218 pages. Available in PDF, EPUB and Kindle. Book excerpt: Prostate cancer (PCa) is the second most lethal cancer in men with a five year survival rate of only 30 percent. However, it is from metastases to the lung, bone, and lymph that patients will die, not from the primary prostatic cancer. In order to create treatments for this lethal form, researchers need a reliable model that emulates human progression of the disease. Over the last 15 years, there has been great progress made in genetically engineered mouse models using androgen-driven promoters to force oncogene expression. However, these models are not useful in the study of androgen independent PCa, from which most metastases derive. Additionally, existing models do not develop metastases to bone or lung that are common in human PCa. To improve on existing mouse PCa models, a mouse overexpressing the oncogene MYC with loss of the tumor suppressor PTEN under the control of Hoxb13 regulatory elements, termed BMPC, was developed. This model, which involves breeding together three separate transgenic mouse strains, develops adenocarcinoma by 12 weeks of age with metastases in essentially all cases. However, to be useful as a pre-clinical model additional aspects must be included for imaging along with a simplification of the breeding. The goal of my Master’s thesis project is to genetically simplify the BMPC model, and to add a new functionality in the form of human prostate specific membrane antigen (PSMA) expression. This will be accomplished by expressing the proteins through a single transgene using the “self-cleaving” ability of foot and mouth disease virus-derived 2A peptide proteins. Transgenic mice carrying this multifunctional BAC will be derived and characterized in terms of gene expression and function. This model can be used to study the efficacy of treatments such as targeted nanoparticle delivery, a developing method of clinical cancer treatment.
