Treatment of Mestastatic Breast Cancer by Photodynamic Therapy Induced Anti-Tumor Immunity in a Murine Model PDF Download

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Languages : en
Pages : 13

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One in 8 women in the United States will develop breast cancer during her lifetime. Deaths are due to tumors that have metastasized. Photodynamic therapy (PDT) is a promising cancer treatment in which a photosensitizer (PS) accumulates in tumors and is subsequently activated by visible light of an appropriate wavelength. PDT produces cell death and tumor ablation. Mechanisms include cytotoxicity to tumor cells, shutting down of the tumor vasculature, and the induction of a host immune response. Mechanisms involved in the PDT-mediated induction of anti-tumor immunity are not yet understood. Potential contributing factors are alterations in the tumor microenvironment via stimulation of proinflammatory cytokines and direct effects of PDT on the tumor that increase immunogenicity. We have studied PDT of 410.4 variant 4T1 tumors growing in the mammary fat pad (orthotopic) in Balb/c mice and which produce metastasis. We have shown that a PDT regimen that produces vascular shutdown and tumor necrosis leads to initial tumor ablation but the tumors recur at the periphery. We studied the combination of PDT with immunostimulating therapies. Low dose cyclophosphamide is a mechanism to deplete regulatory T cells; these cells play a role in the immunosuppression activity of tumors. In combination with PDT, cyclophosphamide increases the survival. The second alternative therapy is the use of a novel combination of the immunostimulant CpG Oligodeoxynucleotides (CpG-ODN) and PDT. CpG-ODN directly or indirectly triggers B cells, NK cells, macrophages and dendritic cells to proliferate, mature and secrete cytokines, chemokines and immunoglobulins. Both these novel combinations gave significantly enhanced therapeutic benefit not seen with single treatments alone. We propose that a rational choice of immune stimulant is an ideal addition to PDT regimens.

Author: Edith Njeri Kabingu
Publisher:
ISBN: 9780542999611
Category :
Languages : en
Pages : 148

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Most cancer patients get standard therapies such as chemotherapy and radiation to treat their disease. These therapies are however mainly efficient in targeting the primary tumor and not metastatic disease. Immunotherapeutic strategies to target both primary and disseminated disease have been explored over the years. Photodynamic therapy (PDT) has been explored as a way to target the host's immune defenses to eradicate tumors. PDT is an established therapy for the treatment of various types of cancer. It uses a combination of light and photosensitizing drugs to induce damage to tumor tissue. Pre-clinical and clinical studies have shown that tumor control by PDT correlates with induction of anti-tumor immunity and suggest that the enhanced anti-tumor response may be effective against distant tumors. We have tested this hypothesis by measuring the ability of tumor bearing mice treated with PDT to control tumors outside the local treatment field. Two models were used to address this hypothesis. An experimental metastases model (EMT6) and a spontaneous metastases model (4T1). Using the experimental metastases model we have shown that in situ PDT of subcutaneous tumors of mice bearing both subcutaneous EMT6 mammary tumors and lung tumors results in a significant reduction in the number of lung tumors (an average of 6.5 +/- 3.9 tumors/lung) compared to mice whose subcutaneous tumors were surgically removed (an average of 41.2 +/- 8.5 tumors/lung). This control of tumors outside the field of treatment depended on treatment of tumors in the field because treatment of tumor free areas in tumor bearing mice did not result in control of tumors outside the treatment field. Furthermore, the ability to control these tumors depended upon CD8+ cells and appeared to be independent of CD4+ cells, as tumor control was maintained in mice depleted of CD4 expressing cells and SCID mice receiving CD8+ cells alone prior to PDT were able to control the growth of tumors outside the treatment field. In addition, the memory response did not appear to require CD4 + T cells since SCID mice inoculated with CD8+ were tumor free when challenged with EMT6 tumors 40 days after PDT treatment of primary EMT6 tumors. The mechanism by which this CD8+ T cell response may happen without CD4+ T cell help may be driven by NK cells because NK depleted SCID mice that were reconstituted with CD8 + T cells could not control distant EMT6 tumors following local PDT whereas those not depleted of NK cells but reconstituted with CD8+ T cells could. However the spontaneous metastases 4T1 model did not give us the same kind of results. The 4T1 model proved difficult to treat with PDT. There was no significant change in the number of spontaneous lung metastases after PDT of the primary tumor. A comparative study to investigate differences in PDT responses of 4T1 tumors compared to EMT6 tumors revealed that there may be immune suppression by regulatory T cells in 4T1 tumors. IL-6 production also appears to be enhanced after PDT of 4T1 tumors compared to EMT6 tumors (over 3 fold higher at the 8h time point). This could be driving proliferation and survival of 4T1 tumors. The expression of Bcl-2 in 4T1 and not EMT6 tumors and Bax in EMT6 and not 4T1 tumors supports the possibility that 4T1 tumors are protected from death and hence their inability to be killed by PDT. These studies suggest that in some tumors, PDT can be a potential immunotherapeutic strategy for controlling distant disease through induction of a specific host anti-tumor immune response mediated by CD8+ T cells. PDT may however not work for all tumors, but understanding differences in the response of various tumors may contribute to the development of strategies to overcome suppressive mechanisms.

Author: Minan Wang
Publisher:
ISBN:
Category :
Languages : en
Pages : 123

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Photodynamic therapy (PDT) has long been shown to be capable of killing malignant cells, causing shut down of tumor microvasculature, and induction of host immune response. The therapeutic efficacy of PDT is dependent on CD8+ T cells. Activation of tumor-antigen-specific CD8+ T cells requires cross-presentation and cross-priming by dendritic cells (DCs). The cytokine secretion profile of DCs dictates different CD4+ T cell responses, which are critical for CD8+ T cell differentiation and activation. However, the development of CD4+ T cells in the setting of PDT treatment is unclear and controversial. Therefore, to improve PDT efficacy in treating aggressive and metastatic disease, it is imperative to understand the mechanisms of how PDT treatment activates DCs, triggers T cell responses, and the role of responding T cells in PDT efficacy and induction of anti-tumor immunity. We show that PDT-generated tumor cell lysate (PDTTCL) can activate bone marrow-derived dendritic cells (BMDCs) efficiently by upregulation of co-stimulatory molecules and induction of pro-inflammatory cytokines as well as chemokines that are critical mediators for shaping anti-tumor immune response by enhancing CD8+ T cell responses. IL-1©Ø is required for DC cross-priming of interferon (IFN)-©Đ-producing CD8+ T cells by PDTTCL. PDTTCL-induced IL-1©Ø is produced in a toll-like receptor (TLR)-dependent but NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-inflammasome-independent pathway. In addition, PDTTCL induction of IL-1©Ø precursor synthesis is also dependent upon serine proteases. Our results revealed that PDTTCL induces IL-1©Ø maturation in a novel signaling pathway dependent on membrane-bound protease(s). We found that NF-©®B plays a dual role in PDT induction of IL-1©Ø synthesis and activation.^Our study contributes to the mechanisms of how PDT enhances tumor cell immunogenicity to promote DC activation, providing the potential means to optimize CD8+ T cell responses and improve clinical PDT efficacy. The mechanisms of how IL-1©Ø contributes to PDT efficacy are not fully understood. In addition to its critical role in DC cross-priming of CD8+ T cells, IL-1©Ø also plays a vital role in Th17 cell differentiation and development. We further investigated the poorly characterized CD4+ T cell responses elicited by PDT. CD4+ T cell lineage differentiation is driven by cytokines generated after DC activation. By examining the cytokine profile of PDTTCL stimulated BMDCs, we found a novel CD4+ Th17 cell response following in situ PDT treatment. The major cytokine secreted by Th17 cells is IL-17, which plays a crucial role in PDT-induced antitumor immunity. A better understanding about how DCs are matured and activated by PDTTCL allows us to further exploit PDT in combination with DC vaccine against aggressive tumor model. We significantly improved PDT efficacy in treating aggressive tumor by combining DC vaccine and TLR8/8 agonist, providing promising strategy using PDT to combat secondary disease in clinics. In PDT combination therapy treated tumor bearing mice, we show that the efficacy of PDT combination therapy is dependent on CD4+ T cells, CD8+ T cells and natural killer (NK) cells. Due to the complex cross-talk of DCs, NK and T cells, we believe it is essential to study the role of them at different stages after PDT to better understand how their roles may change during disease progression, and to optimize PDT efficacy by exploiting them appropriately.

Author: Valentina Rapozzi
Publisher: Springer
ISBN: 3319127306
Category : Medical
Languages : en
Pages : 253

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This volume provides a comprehensive review of resistance induced by photodynamic therapy (PDT) in tumor cells. Understanding the underlying mechanisms in this process leads to the improvement of therapeutic modality, in combination with chemotherapy, immunotherapy, and radiotherapy. Photodynamic therapy is a minimally invasive therapeutic procedure that can exert a selective or preferential cytotoxic activity toward malignant cells. The procedure involves administration of an intrinsically non-toxic photosensitizing agent (PS) followed by irradiation at a wavelength corresponding to a visible absorption band of the sensitizer. In the presence of oxygen, a series of events lead to direct tumor cell death, damage to the microvasculature, and induction of a local inflammatory reaction. Studies reveal that PDT can be curative, particularly in early stage tumors and this volume explores the potential of PDT, but also reveals strategic approaches to overcome resistance in tumor cells.

Author: Michael R. Hamblin
Publisher: Artech House
ISBN: 1596932783
Category : Medical
Languages : en
Pages : 601

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With today's focus on targeted and minimally invasive therapies, photodynamic therapy (PDT) is now being studied and used to combat many disease states and to investigate critical biological questions. This groundbreaking resource brings you the latest advances in photodynamic therapy and offers you a solid understanding of the design, delivery and dosimetry of the three basic ingredients of PDT - photosensitizers, light and oxygen. The book covers novel areas of mechanistic and innovative translational approaches. Moreover, it gives you an overview of the important medical applications of PDT, including approved treatments, clinical trials, and investigated therapies for cancer and non-malignant diseases.

Author: Christa Innae Devette
Publisher:
ISBN:
Category :
Languages : en
Pages : 188

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Author: Ruud Weijer
Publisher:
ISBN: 9789462335349
Category :
Languages : en
Pages : 0

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"Photodynamic therapy (PDT) is based on the activation of a photosensitizer by (laser) light to locally produce highly destructive reactive oxygen species. When employed for cancer treatment, PDT is able to induce tumor cell death, microvascular damage, and an anti-tumor immune response. All these factors contribute to tumor destruction. Although PDT is successfully applied for a variety of tumor types, PDT yields promising yet unsatisfactory results in non-resectable perihilar cholangiocarcinoma patients. This is partly due to the use of suboptimal photosensitizers and the activation of survival signaling in PDT-subjected but sublethally afflicted tumor cells. Consequently, the aim of this research was to design a novel PDT strategy to treat these patients in a selective and effective manner. The first part of this thesis focuses on the incorporation of a photosensitizer with superior photochemical properties into a multitargeting liposomal delivery system. The second part analyzes the survival response in PDT-treated tumor cells and in the third part of this thesis we pharmacologically intervened in survival programs to improve therapeutic efficacy."--Samenvatting auteur.

Author: Martijn R. Meijerink
Publisher: Springer
ISBN: 3319551132
Category : Medical
Languages : en
Pages : 281

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This book provides a comprehensive overview of the clinical use of irreversible electroporation (IRE) – better known by its commercial name, NanoKnife – which is one of the most exciting new needle-guided cancer treatments. The coverage includes the history of IRE, general technique, preclinical research, applications in clinical practice and early clinical results, and future perspectives. Contraindications, treatment planning, potential complications, follow-up imaging, and other practical aspects are fully discussed, with highlighting of useful tips and tricks. Through the delivery of short but highly intense electrical pulses, IRE results in tumor cell membrane permeabilization, causing cells to go into apoptosis. The minimally invasive nature of IRE, combined with the prospect of completely eradicating tumors while preserving delicate structures in the ablation zone, makes IRE the object of worldwide clinical research. This book will be of value for practitioners and trainees in interventional and diagnostic radiology, surgery, medical oncology, HPB and gastroenterology, urology, and radiation oncology.

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Languages : en
Pages : 9

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Our preclinical studies in tumor-bearing mice have shown that intratumoral injection of an adenoviral vector expressing interleukin-12 was effective in inducing tumor regression, antitumor immune responses and long term survival without disease relapse in 40% treated animals. Based on these findings, we have developed a Phase I trial of intratumoral delivery of an adenoviral vector (Adv. RSV-hIL12, ADV-hIL12) expressing the human interleukin-12 cDNA in patients with metastatic breast cancer to the liver. We have completed preclinical efficacy and toxicity studies to support an IND application to the FDA to conduct the proposed clinical trial. Revisions to the clinical protocol and consent have been made on the recommendations of the FDA and NIH-OBA. We have successfully completed clinical grade production of the study agent (Adv. RSV-hIL12) in the Vector GMP Facility at Mount Sinai. The IND was approved by the FDA (6/11/02). The revised protocol and consent was submitted to the Department of the Army (6/17/02) for approval. The Human Subjects Protection Division of the Department has granted approval on 10/17/04 after further revisions were made at their request. The clinical trial will be activated for patient accrual once the revisions requested by the HSPD have been approved by the local IRB.

Author:
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ISBN:
Category :
Languages : en
Pages : 18

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The original hypothesis was that blocking DR5 with vaccine-induced antagonist antibodies (Ab) will protect T cells from TRAIL-induced apoptosis and enhance their anti-tumor activity. The three specific aims were to (1) Construct and test DR5 vaccines to induce anti-DR5 Ab (2) Test the antagonist activity of vaccine-induced anti-DR5 Ab and (3) Amplify anti-tumor immunity by DR5 vaccination. We found that immune sera to human DR5 showed significant agonist rather than antagonist activity to induce profound tumor cell apoptosis. Histone deacetylase induced the expression of TRAIL in tumor cells via SP-1 and may be used to complement DR5 vaccination. Furthermore activated T cells were resistant to DR5 mediated apoptosis. Based on these interesting results we will proceed with the revised hypothesis that agonist DR5 Ab induced by DNA vaccination will trigger tumor cell apoptosis without compromising T cell activity. The specific aims are to (1) Construct and test DR5 vaccines to induce anti-DR5 Ab (2) Test the agonist activity of vaccine-induced anti-DR5 Ab and (3) Amplify anti-tumor activity of DR5 vaccination with novel chemotherapeutics.