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Immunological Aspects of Local Radiotherapy: Clinical Relevance

Novel Biological Radiochemotherapy Approaches in Locally Advanced-stage Cervical Cancer Management

Abstract: Biological anticancer agents that enhance radiochemotherapeutic effect are appealing in the modern medical treatment of uterine cervix cancer. In this concise review, the focus is on three classes of biological anticancer agents. The first class is ribonucleotide reductase inhibitors. These biological anticancer agents impede deoxyribonucleotide payout and stop new synthesis of DNA molecule building blocks. By disrupting deoxyribonucleotide supply and demand economics, ribonucleotide reductase inhibitors disrupt the repair of radiation- and chemotherapy-induced DNA damage and enhance cancer cell death. Angiogenesis inhibitors represent a second class of biological anticancer agents. Angiogenesis inhibitors are conceptually thought to normalize cancer tumor vasculature and modulate vascular endothelial growth factor signals. Consequences of normalized tumor vessel permeability are better oxygen supply for radiosensitization and improved tumor fluid dynamics imparting chemosensitization. A third class, cytolytic T-cell immune modulators, edits human immune system responses to cancer cell antigens. These biological anticancer agents exploit molecular signaling involved in immune detection and in immune eradication. Completed and planned clinical trials utilizing these agents are discussed relative to the future radiochemotherapeutic management of uterine cervix cancer. ... Read more

Gene Therapy and Virotherapy: Novel Therapeutic Approaches for Brain Tumors

Abstract: Glioblastoma multiforme (GBM) is a deadly primary brain tumor in adults, with a median survival of ~12-18 months post-diagnosis. Despite recent advances in conventional therapeutic approaches, only modest improvements in median survival have been achieved; GBM usually recurs within 12 months post-resection, with poor prognosis. Thus, novel therapeutic strategies to target and kill GBM cells are desperately needed. Our group and others are pursuing virotherapy and gene therapy strategies for the treatment of GBM. In this review, we will discuss various virotherapy and gene therapy approaches for GBM currently under pre-clinical and clinical evaluation including direct or conditional cytotoxic, and/or immunostimulatory approaches. We also discuss cutting-edge technologies for drug/gene delivery and targeting brain tumors, including the use of stem cells as delivery platforms, the use of targeted immunotoxins, and the therapeutic potential of using GBM microvesicles to deliver therapeutic siRNAs or virotherapies. Finally, various animal models available to test novel GBM therapies are discussed. ... Read more

Advances in Therapeutic Vaccines for Pancreatic Cancer

Abstract: Pancreatic cancer is one of the most difficult-to-treat cancers. Despite surgical resection, radiation and/or chemotherapy, greater than 94% of people with pancreatic cancer do not survive beyond 5 years. In fact, median survival after diagnosis of metastatic pancreatic cancer is 4.5 months. The majority of patients are diagnosed with nonresectable, metastatic disease, and chemotherapy only extends their median survival by less than 2 months with only 18% of those treated surviving beyond 1 year. Despite the severity of their disease, most patients exhibit tumor specific cellular immunity to their pancreatic cancer antigens. Obviously their immunity is ineffective in preventing tumor growth. Recent studies have demonstrated that the tumor microenvironment may hold the key to determining the nature of the tumors' ability to escape from immune attack. Preliminary clinical trials have suggested that blocking these escape mechanisms may result in survival benefit to the patients, and phase I and II clinical trials with tumor vaccines have led to some survival benefits. Perhaps combining therapies directed against immune escape mechanisms with tumor vaccines will result in even greater survival benefit for patients with pancreatic cancer. While therapeutic vaccines for pancreatic cancers have been reviewed previously (Plate, 2011), updates on recent preliminary reports of two clinical vaccine trials are worthy of our attention. ... Read more

GM-CSF-Secreting Vaccines for Solid Tumors: Moving Forward

Abstract: Cancer vaccines consisting of intact tumor cells genetically modified to secrete the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) have undergone extensive preclinical development. These vaccines induce the massive accumulation of dendritic cells at the intradermal injection site, which engulf, process, and present tumor antigens to activate tumor-specific T cells. Early phase clinical testing demonstrated promising evidence of safety and bioactivity, although initial phase III clinical trials were unsuccessful. Together, the preclinical and clinical data argue for the continued clinical development of these vaccines, integrating them with standard and novel cancer therapeutics that enhance vaccine activity by overcoming immune tolerance and suppression, and/or augmenting co-stimulatory pathways of T cell activation. ... Read more

Tracking the Seed and Tending the Soil: Evolving Concepts in Metastatic Breast Cancer

Abstract: Metastasis, the process whereby cancer cells spread from their primary site of origin and grow in adjacent or distant sites, is the primary cause of death in cancer patients. The last 30 years has witnessed significant progress in decreasing cancer mortality rates -- largely as a result of improved screening and prevention, practical applications of cancer genomics, and less toxic, more targeted therapies. Despite these improvements, metastasis relentlessly drives mortality. The pervasive mortality from metastasis highlights the shortcomings of traditionally accepted hypotheses on the metastatic process. Historically, metastasis has been described as a unidirectional process, whereby cancer cells leave a primary tumor and seed metastasis in regional lymph nodes or distant sites. This anatomically based hypothesis has dictated much of our medical, and in particular, surgical approach to treating cancers. Alternatively, recent research indicates that metastasis is a multidirectional process whereby cancer cells can seed distant sites as well as the primary tumor itself. The multidirectional pathway of cancer cells, termed "self-seeding," has been corroborated in several experimental and clinical models. This review will evaluate the "self-seeding" hypothesis with attention both to the "seed" (cancer cells) as well as the "soil" (premetastatic niche). Increasingly, the role of the microenvironment surrounding metastases appears essential to the survival of metastatic colonies. The self-seeding model depends not only on the inherent mobility of cancer cells, but also on the supporting non-cancerous cells which enable circulating tumors cells to migrate to and survive in distant sites. The recognition that some of these non-cancerous cells include key components of the immune system has re-ignited the field of immunotherapy in cancer. One particular area of immunotherapy research, tumor entrained neutrophils, will be reviewed in more depth. Ultimately, understanding the dynamic interplay between cancer cells and the metastatic niche offers fertile ground for progress both in the treatment and prevention of metastasis. ... Read more

Doxorubicin Encapsulated in Micelles Enhances Radiosensitivity in Doxorubicin-resistant Tumor Cells

Abstract: To evaluate the efficacy of doxorubicin (DOX) loaded micelles in enhancing DOX radiosensitivity in DOX-resistant K562 tumor cells (K562/DOX cells), DOX loaded polyethylene glycol-polycaprolactone (PEG-PCL) copolymer micelles and pluronic 105 (P105) micelles, and composite micelles composed of PEG-PCL and P105 were prepared. By using MTT assay, soft agar cloning assays, confocal laser scanning microscopy, and flow cytometry analyses to evaluate the radiosensitivity of each compound, DOX loaded micelles were found to increase the radiosensitivity of K562/DOX cells, as revealed by a marked cellular uptake and its sustained, slower release than free DOX. The micelles encapsulating DOX significantly enhanced its cytotoxicity in K562/DOX cells. Combined treatment with the encapsulation of DOX in micelles and radiotherapy therefore warrants investigation in clinical trials as a potential anticancer strategy with increased efficacy and reduced side effects. ... Read more

Cancer Immunotherapy: Present Status, Future Perspective, and a New Paradigm of Peptide Immunotherapeutics

Abstract: A promising new era of cancer therapeutics with agents that inhibit specific growth stimulatory pathways is finding a new niche in our armamentarium in the war against cancer. Targeted cancer therapeutics, including humanized monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), are amongst the major treatment options for cancer today together with cytotoxic chemotherapies. Targeted therapies are more selective for cancer cells and improve the quality of life for cancer patients undergoing treatment. Many of these drugs have been approved by the FDA, and several more are being studied in clinical trials. Although development of targeted therapeutics has improved cancer treatment significantly, the harsh reality is that the "War on Cancer" still exists. Major challenges still exist with the currently marketed inhibitors, including limitations associated with mAbs and TKIs drug types, acquired mechanisms of drug resistance that cause patient relapse, and tumor heterogeneity. Today, there is an urgent need for the development of novel anti-tumor agents that are cheaper, stable, can selectively target cancer dependent pathways without affecting normal cells, and most importantly, avoid development of resistance mechanisms. Peptide mimics have the potential benefits of being highly selective, stable, cheap, and non-toxic. The focus of this review is to discuss the disadvantages associated with the use of monoclonal antibodies and tyrosine kinase inhibitors. A special emphasis will be placed on efforts taken in our laboratory to 1) design peptide vaccines and therapeutics that target cancer dependent pathways and 2) use a combination approach that will shut down alternative mechanisms that lead to resistance. ... Read more

The Nuclear Epidermal Growth Factor Receptor Signaling Network and Its Role in Cancer

Abstract: The epidermal growth factor receptor (EGFR) is a member of the EGFR family of receptor tyrosine kinases (RTKs). EGFR activation via ligand binding results in signaling through various pathways ultimately resulting in cellular proliferation, survival, angiogenesis, invasion, and metastasis. Aberrant expression or activity of EGFR has been strongly linked to the etiology of several human epithelial cancers including but not limited to head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), breast cancer, pancreatic cancer, and brain cancer. Thus intense efforts have been made to inhibit the activity of EGFR by designing antibodies against the ligand binding domains (cetuximab and panitumumab) or small molecules against the tyrosine kinase domain (erlotinib, gefitinib, and lapatinib). Although targeting membrane-bound EGFR has shown benefit, a new and emerging role for EGFR is now being elucidated. In this review we will summarize the current knowledge of the nuclear EGFR signaling network, including how it is trafficked to the nucleus, the functions it serves in the nucleus, and how these functions impact cancer progression, survival, and response to chemotherapeutics. ... Read more

Adoptive T Cell Immunotherapy Strategies for the Treatment of Patients with Ovarian Cancer

Abstract: Ovarian cancer is the leading cause of cancer death among gynecological malignances. Despite the initial successful multimodality therapy with cytoreductive surgery and subsequent combination chemotherapy, most patients with advanced disease will ultimately relapse and become incurable. For this reason novel therapeutic approaches for the treatment of this malignancy are urgently needed. Adoptive transfer of genetically modified autologous tumor-reactive T cells is a promising novel antitumor therapy for many cancers. T cells may be genetically modified ex vivo to express chimeric antigen receptors (CARs), which are artificial T cell receptors targeted to specific tumor antigens. The resulting T cells are thus programmed to recognize tumor cells. Ovarian carcinomas in particular appear to be suited to this therapeutic approach based on the fact that these tumors are relatively immunogenic, inducing an endogenous T cell response. Furthermore, the degree to which this endogenous T cell mediated immune response is evident correlates to long-term patient prognosis following surgery and chemotherapy. To this end, adoptive T cell immunotherapy strategies for the treatment of ovarian carcinomas appear to be particularly promising and are currently being investigated at several centers in both pre-clinical and clinical settings. ... Read more

Advances in Cellular Therapy for the Treatment of Leukemia

Abstract: Adoptive immunotherapy in the form of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a treatment modality for acute and chronic leukemias that has been in practice for several decades. Drawbacks to transplantation include toxicity from chemotherapy/radiation conditioning regimens, additional toxicity from graft versus host disease, and reliance on appropriate human leukocyte antigen matched donors. Newer modalities with increased specificity of donor cells to tumor cells in addition to therapies that do not require engraftment for anti-tumor effect reduce the risk of graft versus host disease and may create a more robust graft versus leukemia response. Without the need for engraftment, or at the very least in the absence of a 100% engraftment requirement, conditioning regimens may be minimized. Three methods of adoptive immunotherapy that may offer some of these advantages over traditional transplantation are donor lymphocyte infusions (DLI), chimeric antigen receptor modified T cells (CAR T cells), and cellular immunotherapy. DLIs and cellular therapy consist of transfusing T lymphocytes from the donor to recipient in an unmanipulated form. Alternatively, donor T lymphocytes can be modified with addition of chimeric antigen receptors for specific antigen directed killing of tumor cells. Significant responses and survival benefit have been reported with these modalities. Herein, we review the mechanisms for these newer adoptive immune therapies, clinical indications for their use, and potential future directions. ... Read more

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