Biological Therapy Of Cancer Research Articles

Theranostic Potential of Oncolytic Vaccinia Virus

Biological cancer therapies, such as oncolytic, or replication-selective viruses have advantages over traditional therapeutics as they can employ multiple different mechanisms to target and destroy cancers (including direct cell lysis, immune activation and vascular collapse). This has led to their rapid recent clinical development. However this also makes their pre-clinical and clinical study complex, as many parameters may affect their therapeutic potential and so defining reason for treatment failure or approaches that might enhance their therapeutic activity can be complicated. The ability to non-invasively image viral gene expression in vivo both in pre-clinical models and during clinical testing will considerably enhance the speed of oncolytic virus development as well as increasing the level and type of useful data produced from these studies. Further, subsequent to future clinical approval, imaging of reporter gene expression might be used to evaluate the likelihood of response to oncolytic viral therapy prior to changes in tumor burden. Here different reporter genes used in conjunction with oncolytic viral therapy are described, along with the imaging modalities used to measure their expression, while their applications both in pre-clinical and clinical testing are discussed. Possible future applications for reporter gene expression from oncolytic viruses in the phenotyping of tumors and the personalizing of treatment regimens are also discussed.

Progress and Challenges in Colorectal Cancer Screening

Although faecal and endoscopic tests appear to be effective in reducing colorectal cancer incidence and mortality, further technological and organizational advances are expected to improve the performance and acceptability of these tests. Several attempts to improve endoscopic technology have been made in order to improve the detection rate of neoplasia, especially in the proximal colon. Based on the latest evidence on the long-term efficacy of screening tests, new strategies including endoscopic and faecal modalities have also been proposed in order to improve participation and the diagnostic yield of programmatic screening. Overall, several factors in terms of both efficacy and costs of screening strategies, including the high cost of biological therapy for advanced colorectal cancer, are likely to affect the cost-effectiveness of CRC screening in the future.

Modern pharmacological therapy of breast cancer

Healthy lifestyle, population-based screening mammography and modern medical-oncological treatment in specialized breast cancer centers are the basic elements of the fight against breast cancer mortality. Treatment plan for the individual patient should be recommended by multidisciplinary oncoteam before initiating definitive therapy. Strategy of the medical-oncological therapy of breast cancer is determined by the biological features and stage of the tumor. The most important biological features are endocrine sensitivity, Human Epidermal Growth Factor Receptor 2 status and proliferative capability of the tumor. In this review the strategy of medical-oncological treatment (chemotherapy, endocrine therapy, targeted biological therapy) of breast cancer is presented, based on receptor status and proliferative capability of the tumor in various stages of the disease.

Graphene Oxide–Polyethylenimine Nanoconstruct as a Gene Delivery Vector and Bioimaging Tool

Graphene oxide (GO) has attracted an increasing amount of interest because of its potential applications in biomedical fields such as biological imaging, molecular imaging, drug/gene delivery, and cancer therapy. Moreover, GO could be fabricated by modifying its functional groups to impart specific functional or structural attributes. This study demonstrated the development of a GO-based efficient gene delivery carrier through installation of polyethylenimine, a cationic polymer, which has been widely used as a nonviral gene delivery vector. It was revealed that a hybrid gene carrier fabricated by conjugation of low-molecular weight branched polyethylenimine (BPEI) to GO increased the effective molecular weight of BPEI and consequently improved DNA binding and condensation and transfection efficiency. Furthermore, this hybrid material facilitated sensing and bioimaging because of its tunable and intrinsic electrical and optical properties. Considering the extremely high transfection efficiency comparable to that of high-molecular weight BPEI, high cell viability, and its application as a bioimaging agent, the BPEI-GO hybrid material could be extended to siRNA delivery and photothermal therapy.

Cell-based delivery of oncolytic viruses

Oncolytic viruses,a novel class of virus vectors,which selectively replicate only in tumor cells,have excellent tumor targeting and good tansfection efficiency.Many oncolytic viruses have apparent curative effect when administered intratumorally.However,the host immune system remains a critical obstacle to systemic administration of virotherapeutics.It appears that cell-based delivery of oncolytic viruses could offer one solution to this critical problem,which provides a new platform to the biological therapy of cancer. Key words: Oncolytic viruses ; Neoplasms ; Therapy ;

SITC/iSBTc Cancer Immunotherapy Biomarkers Resource Document: Online resources and useful tools - a compass in the land of biomarker discovery

Recent positive clinical results in cancer immunotherapy point to the potential of immune-based strategies to provide effective treatment of a variety of cancers. In some patients, the responses to cancer immunotherapy are durable, dramatically extending survival. Extensive research efforts are being made to identify and validate biomarkers that can help identify subsets of cancer patients that will benefit most from these novel immunotherapies. In addition to the clear advantage of such predictive biomarkers, immune biomarkers are playing an important role in the development, clinical evaluation and monitoring of cancer immunotherapies. This Cancer Immunotherapy Resource Document, prepared by the Society for Immunotherapy of Cancer (SITC, formerly the International Society for Biological Therapy of Cancer, iSBTc), provides key references and online resources relevant to the discovery, evaluation and clinical application of immune biomarkers. These key resources were identified by experts in the field who are actively pursuing research in biomarker identification and validation. This organized collection of the most useful references, online resources and tools serves as a compass to guide discovery of biomarkers essential to advancing novel cancer immunotherapies.

Interleukin-15 and tumor

Interleukin-15 is a multffunctional cytokine,which are the activating and induction factors of the T-cell,B-cell,NK-cell and lymphokine-activated killer cell (LAK).It can stimulate hematopoietic stem cell proliferation and differentiation,enhance immunity and has anti-tumor effects.IL-15 and IL-2 have similar structures and functions,but many activating effects of IL-15 are stronger than the other's.IL-15 is closely related to tumor development,and has broad application prospects in biological therapy of cancer. Key words: Interleukin-15 ; Neoplasms ; Cytokines ;

The significance of expression of autophagy-related gene Beclin, Bcl-2, and Bax in breast cancer tissues

The purpose of this study was to detect the expression of autophagy-related gene Beclin1 and apoptosis-related genes Bcl-2 and Bax in breast cancer tissues, to investigate their relationship and significance to the occurrence and development of breast cancer, and to provide an experimental basis for the biological treatment of breast cancer in the future. Human breast cancer tissues and relatively healthy breast tissue adjacent to the tumor were collected during surgical resection. By using RT-PCR and western blot, the mRNA and protein expressions of Beclin1, Bcl-2, and Bax were detected in the breast cancer tissues and the relatively healthy, adjacent tissues. The correlations of these expressions with the occurrence, development, and clinicopathology of breast cancer were analyzed. The mRNA and protein expressions of Beclin1 and Bcl-2 in breast cancer tissues were significantly lower than those in the relatively healthy, adjacent breast tissues (p < 0.05); the lower the degree of tumor differentiation, the lower the mRNA and protein expressions of Beclin1 and Bcl-2 (p < 0.05); the mRNA and protein expressions of Beclin1 and Bcl-2 in breast cancer tissues from patients positive for lymph node metastasis were significantly lower than those negative for lymph node metastasis (p < 0.05); the mRNA and protein expressions of Beclin1 and Bcl-2 in breast cancer tissues from patients positive for distant metastasis were significantly lower than those negative for distant metastasis (p < 0.05); the mRNA and protein expressions of Beclin1 and Bcl-2 in breast cancer tissues from patients positive for ki67 were significantly lower than those negative for ki67 (p < 0.05). The mRNA and protein expressions of Bax were different from those of Beclin1 and Bcl-2. In breast cancer tissues, the mRNA and protein expressions of Bax were up-regulated (p < 0.05); the lower the degree of tumor differentiation, the higher the mRNA and protein expressions of Bax (p < 0.05); the mRNA and protein expressions of Bax in breast cancer tissues from patients positive for lymph node metastasis were significantly higher than those negative for lymph node metastasis (p < 0.05); and the mRNA and protein expressions of Bax in breast cancer tissues from patients positive for distant metastasis were significantly higher than those in patients negative for distant metastasis (p < 0.05). However, the mRNA and protein expressions of these three genes were not correlated with patient age, tumor size, progesterone receptor positivity, or human epidermal growth factor positivity (p > 0.05). The correlation of Bcl-2 and Bax mRNA with Beclin1 mRNA expressed in breast cancer tissues were both statistically significant (p < 0.05). The activity change of autophagy and apoptosis is associated with the tumorigenesis and tumor progression of breast cancer. The joint detection of these three genes (Beclin1, Bcl-2, and Bax) contributes to the early diagnosis of and predicts prognosis for breast cancer, and this also provides an experimental basis for the biological therapy of breast cancer.

Review of the 25th annual scientific meeting of the International Society for Biological Therapy of Cancer

Led by key opinion leaders in the field, the 25th Annual Meeting of the International Society for Biological Therapy of Cancer (iSBTc, recently renamed the Society for Immunotherapy of Cancer, SITC) provided a scientific platform for ~500 attendees to exchange cutting-edge information on basic, clinical, and translational research in cancer immunology and immunotherapy. The meeting included keynote addresses on checkpoint blockade in cancer therapy and recent advances in therapeutic vaccination against cancer induced by Human Papilloma Virus 16. Participants from 29 countries interacted through oral presentations, panel discussions, and posters on topics that included dendritic cells and cancer, targeted therapeutics and immunotherapy, innate/adaptive immune interplay in cancer, clinical trial endpoints, vaccine combinations, countering negative regulation, immune cell trafficking to tumor microenvironment, and adoptive T cell transfer. In addition to the 50 oral presentations and >180 posters on these topics, a new SITC/iSBTc initiative to create evidence-based Cancer Immunotherapy Guidelines was announced. The SITC/iSBTc Biomarkers Taskforce announced the release of recommendations on immunotherapy biomarkers and a highly successful symposium on Immuno-Oncology Biomarkers that took place on the campus of the National Institutes of Health (NIH) immediately prior to the Annual Meeting. At the Annual Meeting, the NIH took the opportunity to publicly announce the award of the U01 grant that will fund the Cancer Immunotherapy Trials Network (CITN). In summary, the Annual Meeting gathered clinicians and scientists from academia, industry, and regulatory agencies from around the globe to interact and exchange important scientific advances related to tumor immunobiology and cancer immunotherapy.

Pioneering the trail of cancer immunotherapy

The annual conference of the International Society for Biological Therapy of Cancer (iSBTc), recently renamed the Society for Immunotherapy of Cancer (SITC), provides clinicians and scientists with a uniquely broad yet focused view of the growing field of tumor immunology and cancer immunotherapy. In this time of exciting new developments in cancer immunotherapy, it is critically important to effectively guide new immune-based advances from bench to bedside to improve outcomes of patients with cancer. iSBTc/SITC with its dedicated leadership (past and present) provides this guidance through its Annual Meeting and associated programs. This year the society celebrated its 25th Anniversary in Hyatt Regency Washington on Capitol Hill (Washington DC, USA), with educational offerings from 30 September to 4 October 2010.

Abstracts From the 25th Annual Scientific Meeting of the International Society for Biological Therapy of Cancer (now the Society for Immunotherapy of Cancer)

Abstracts From the 25th Annual Scientific Meeting of the International Society for Biological Therapy of Cancer (now the Society for Immunotherapy of Cancer)

The iSBTc/SITC primer on tumor immunology and biological therapy of cancer: a summary of the 2010 program

The Society for Immunotherapy of Cancer, SITC (formerly the International Society for Biological Therapy of Cancer, iSBTc), aims to improve cancer patient outcomes by advancing the science, development and application of biological therapy and immunotherapy. The society and its educational programs have become premier destinations for interaction and innovation in the cancer biologics community. For over a decade, the society has offered the Primer on Tumor Immunology and Biological Therapy of Cancer™ in conjunction with its Annual Scientific Meeting. This report summarizes the 2010 Primer that took place October 1, 2010 in Washington, D.C. as part of the educational offerings associated with the society's 25th anniversary. The target audience was basic and clinical investigators from academia, industry and regulatory agencies, and included clinicians, post-doctoral fellows, students, and allied health professionals. Attendees were provided a review of basic immunology and educated on the current status and most recent advances in tumor immunology and clinical/translational caner immunology. Ten prominent investigators presented on the following topics: innate immunity and inflammation; an overview of adaptive immunity; dendritic cells; tumor microenvironment; regulatory immune cells; immune monitoring; cytokines in cancer immunotherapy; immune modulating antibodies; cancer vaccines; and adoptive T cell therapy. Presentation slides, a Primer webinar and additional program information are available online on the society's website.

Non-Invasive Radiofrequency-Induced Targeted Hyperthermia for the Treatment of Hepatocellular Carcinoma

Targeted biological therapies for hepatocellular cancer have shown minimal improvements in median survival. Multiple pathways to oncogenesis leading to rapid development of resistance to such therapies is a concern. Non-invasive radiofrequency field-induced targeted hyperthermia using nanoparticles is a radical departure from conventional modalities. In this paper we underscore the need for innovative strategies for the treatment of hepatocellular cancer, describe the central paradigm of targeted hyperthermia using non-invasive electromagnetic energy, review the process of characterization and modification of nanoparticles for the task, and summarize data from cell-based and animal-based models of hepatocellular cancer treated with non-invasive RF energy. Finally, future strategies and challenges in bringing this modality from bench to clinic are discussed.

New Dietary Supplements from Medicinal Mushrooms: Dr Myko San—A Registration Report

In December 2010 the Ministry of Health and Social Welfare of the Republic of Croatia registered tablet preparations AGARIKON. 1 and MYKOPROTECT. 1, developed by Dr Myko San-Health From Mushrooms Co., as dietary supplements. This may be the first time for a European manufacturer to successfully register its own medicinal mushroom products in a European country. As a product with a very broad spectrum of action, officially described as a preparation for immunity strengthening and general health improvement, AGARIKON.1 is a result of 20 years of research and practice, and is based on the formulation that has achieved the best tumor growth inhibition rates-above 90% on tumor cell lines of mouse squamous cell carcinoma and fibrosarcoma. Since the usage of massive dosages of proprietary blended liquid mushroom extracts in patients with breast, colorectal, lung, and other cancers significantly improved their survival rates, alleviated side effects of standard oncological therapies, improved their quality of life, and resulted in life prolongation-the very idea is that scientifically verified medicinal mushroom products can be used as powerful biological weapons to fight human malignancies. If progressive modem medicine were redefined in a more effective and humane way, cancer mycotherapy should be a part of a broad concept of biological prevention and therapy of cancer. Also, with a very broad spectrum of action, generally formulated as "to strengthen immunity," MYKOPROTECT. 1 is intended as an important element in the prevention and fighting of serious viral infections, whether they are caused by well-known viruses (hepatitis, HIV, etc.) or newly emerging ones.

Immuno-Oncology biomarkers 2010 and beyond: Perspectives from the iSBTc/SITC biomarker task force

The International Society for Biological Therapy of Cancer (iSBTc, recently renamed the Society for Immunotherapy of Cancer, SITC) hosted a one-day symposium at the National Institutes of Health on September 30, 2010 to address development and application of biomarkers in cancer immunotherapy. The symposium, titled Immuno-Oncology Biomarkers 2010 and Beyond: Perspectives from the iSBTc/SITC Biomarker Task Force, gathered approximately 230 investigators equally from academia, industry and governmental/regulatory agencies from around the globe for panel discussions and presentations on the following topics: 1) immunologic monitoring: standardization and validation of assays; 2) correlation of immunity to biologic activity, clinical response and potency assays; 3) novel methodologies for assessing the immune landscape: clinical utility of novel technologies; and 4) recommendations on incorporation of biomarkers into the clinical arena. The presentations are summarized in this report; additional program information and slides are available online at the iSBTc/SITC website.

Rituximab Inhibits the PI3K/Akt Survival Pathway In B-NHL Cells Via Induction of the PTEN Tumor Suppressor: Pivotal Roles of the Inhibition of the PTEN Repressors Snail and YY1

AbstractAbstract 3152We have reported that treatment of B-NHL cell lines with rituximab resulted in the inhibition of the constitutively activated PI3K-AKT pathway (Suzuki et al., Oncogene 26:6184, 2007). Examination of the mechanism by which rituximab inhibits the PI3K/Akt pathway revealed that it induces the expression of the PI3K/Akt inhibitor PTEN (phosphatase and tensin homolog detected on chromosome 10). Time kinetic analysis indicated that the induction of PTEN occurs as early as 6 h post-rituximab treatment. The objective of this study is to delineate the molecular mechanism by which PTEN is induced by rituximab. We hypothesized that rituximab-induced inhibition of the constitutively activated NF-κB pathway, directly and indirectly through inhibition of the PI3K/Akt pathway, may result in the inhibition downstream of the PTEN transcription factors and repressors, Snail and Yin Yang 1 (YY1). Snail has been reported to repress the transcription of PTEN (Escriva, M et al., Mol Cell Biol 28:1528, 2008). Also, YY1 has been reported to positively regulate Snail transcription and expression (Palmer, MB et al., Mol Cancer Res 7:221, 2009). In addition, the induction of PTEN by rituximab also results, in a feed-back loop, in the suppression of YY1 and Snail and potentiates the induction of PTEN (Petriella et al, Cancer Biology Therapy, 8, 1389, 2009). This hypothesis was tested using the B-NHL Ramos cells, as model, for these studies. Treatment of Ramos with rituximab (20ug/ml for 16 hours) resulted in the inhibition of NF-κB, Snail, and YY1 and induction of PTEN expression as assessed by western. The direct role of Snail and YY1 in the suppression of PTEN expression was demonstrated in cells transfected with Snail or YY1 siRNA. The treated cells demonstrated significant induction of PTEN and, concomitantly, inhibition of the PI3K/Akt pathway. We have reported that rituximab sensitizes B-NHL cells to apoptosis by various chemotherapeutic drugs and demonstrated that inhibition of the PI3K/Akt pathway by various inhibitors mimics rituximab in the sensitization of the tumor cells to apoptosis by chemotherapeutic drugs (Suzuki et al., Oncogene 26:6184, 2007). The role of PTEN induction by rituximab in the sensitization of resistanr B-NHL cells to drug-apoptosis was demonstrated in cells pre-treated with rituximab (to induce PTEN) and then transfected with PTEN siRNA. The transfected cells were resistant to drug-induced apoptosis compared to the control siRNA treated cells. Altogether, the above findings demonstrate that rituximab-induced inhibition of the PI3K/Akt pathway is due, in part, to the induction of PTEN through rituximab-induced inhibition of the PTEN repressors Snail and YY1, downstream of NF-κB. Thus, the induction of PTEN by rituximab plays a major role in the reversal of tumor cell resistance to chemotherapeutic drugs. Further, the findings reveal that the dysregulated PI3K/Akt/NF-κB/Snail/YY1/PTEN loop in B-NHL cells can be interfered by rituximab. This interference leads to the inhibition of cell survival and reversal of resistance through sensitization to drugs. We propose that the gene products in this loop are potential novel therapeutic targets in the treatment of lymphoma. Disclosures:No relevant conflicts of interest to declare.

Abstracts for the 25th Annual Scientific Meeting of theInternational Society for Biological Therapy of Cancer

Abstracts for the 25th Annual Scientific Meeting of theInternational Society for Biological Therapy of Cancer

Denaturing capillary electrophoresis for automated detection of L858R mutation in exon 21 of the epidermal growth factor receptor gene in prediction of the outcome of lung cancer therapy

The presence of activating mutations within the tyrosine kinase domain of the epidermal growth factor receptor gene has been attributed to a positive response to biological therapy of lung cancer by small-molecular tyrosine kinase inhibitors, gefitinib and erlotinib. Among the two most significant mutation types are deletions in exon 19 and a single point substitution in exon 21 (termed L858R). The exon 19 deletions can readily be examined by fragment analysis, due to the characteristic length difference between the normal and mutated PCR product. Analysis of the L858R point mutation, however, presents a greater challenge. The current paper is aimed at developing a sensitive, yet simple, low-cost mutation detection assay directed at the L858R mutation using a method based on CE of heteroduplexes under partial denaturing conditions. We perform optimization of separation conditions on different commercial instruments including ones equipped with 8, 16 and 96 capillaries. We present normalized migration reproducibility in the range from 1 (8 and 16) to 5% (96) RSD. A reliable distinction of the R836R silent polymorphism from a potential presence of the L858R mutation is also demonstrated. In its implementation, the presented assay is just another application running on a conventional CE platform without the need of dedicated instrumentation.

Establishment of a novel monoclonal antibody against LGR5

LGR5 is an orphan G-protein-coupled receptor (GPCR) that is expressed on the cell surface membrane. LGR5 is reported to be overexpressed in colon, liver, and ovary tumor compared to normal tissue. However, a specific ligand for LGR5 has not yet been determined, and the function is still not clear. An LGR5-specific monoclonal antibody (mAb) is needed as a tool for detection and analysis of LGR5 biological function and cancer therapy. To date, no mAb against LGR5 that retains high affinity and specificity has been reported. Here, we report successful establishment and characterization of a mAb (KM4056) that specifically recognizes the extracellular N-terminal domain of human LGR5, but not LGR4 or LGR6. This mAb has potent complement-dependent cytotoxicity (CDC) activity in vitro and shows strong anti-tumor activity in vivo against xenograft model by transplanting LGR5 expressing CHO transfectants into SCID mice. Thus, KM4056 can be a useful tool for detection of LGR5 positive cells and analysis of LGR5 biological function.

Immunotherapy of malignant disease with tumor antigen-specific monoclonal antibodies.

A few tumor antigen (TA)-specific monoclonal antibodies (mAb) have been approved by the Food and Drug Administration for the treatment of several major malignant diseases and are commercially available. Once in the clinic, mAbs have an average success rate of approximately 30% and are well tolerated. These results have changed the face of cancer therapy, bringing us closer to more specific and more effective biological therapy of cancer. The challenge facing tumor immunologists at present is represented by the identification of the mechanism(s) underlying the patients' differential clinical response to mAb-based immunotherapy. This information is expected to lead to the development of criteria to select patients to be treated with mAb-based immunotherapy. In the past, in vitro and in vivo evidence has shown that TA-specific mAbs can mediate their therapeutic effect by inducing tumor cell apoptosis, inhibiting the targeted antigen function, blocking tumor cell signaling, and/or mediating complement- or cell-dependent lysis of tumor cells. More recent evidence suggests that TA-specific mAb can induce TA-specific cytotoxic T-cell responses by enhancing TA uptake by dendritic cells and cross-priming of T cells. In this review, we briefly summarize the TA-specific mAbs that have received Food and Drug Administration approval. Next, we review the potential mechanisms underlying the therapeutic efficacy of TA-specific mAbs with emphasis on the induction of TA-specific cellular immune responses and their potential to contribute to the clinical efficacy of TA-specific mAb-based immunotherapy. Lastly, we discuss the potential negative effect of immune escape mechanisms on the clinical efficacy of TA-specific mAb-based immunotherapy.