scholarly journals Virotherapy in Germany—Recent Activities in Virus Engineering, Preclinical Development, and Clinical Studies

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1420
Author(s):  
Dirk M. Nettelbeck ◽  
Mathias F. Leber ◽  
Jennifer Altomonte ◽  
Assia Angelova ◽  
Julia Beil ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Targeted Delivery ◽  
Viral Vector ◽  
Checkpoint Inhibitors ◽  
Therapeutic Proteins ◽  
Cancer Therapeutics ◽  
Cell Killing ◽  
Oncolytic Viruses ◽  
Preclinical Research ◽  
Research Activities

Virotherapy research involves the development, exploration, and application of oncolytic viruses that combine direct killing of cancer cells by viral infection, replication, and spread (oncolysis) with indirect killing by induction of anti-tumor immune responses. Oncolytic viruses can also be engineered to genetically deliver therapeutic proteins for direct or indirect cancer cell killing. In this review—as part of the special edition on “State-of-the-Art Viral Vector Gene Therapy in Germany”—the German community of virotherapists provides an overview of their recent research activities that cover endeavors from screening and engineering viruses as oncolytic cancer therapeutics to their clinical translation in investigator-initiated and sponsored multi-center trials. Preclinical research explores multiple viral platforms, including new isolates, serotypes, or fitness mutants, and pursues unique approaches to engineer them towards increased safety, shielded or targeted delivery, selective or enhanced replication, improved immune activation, delivery of therapeutic proteins or RNA, and redirecting antiviral immunity for cancer cell killing. Moreover, several oncolytic virus-based combination therapies are under investigation. Clinical trials in Germany explore the safety and potency of virotherapeutics based on parvo-, vaccinia, herpes, measles, reo-, adeno-, vesicular stomatitis, and coxsackie viruses, including viruses encoding therapeutic proteins or combinations with immune checkpoint inhibitors. These research advances represent exciting vantage points for future endeavors of the German virotherapy community collectively aimed at the implementation of effective virotherapeutics in clinical oncology.

scholarly journals Aptamers: Novel Therapeutics and Potential Role in Neuro-Oncology

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2889
Author(s):  
Paola Amero ◽  
Soumen Khatua ◽  
Cristian Rodriguez-Aguayo ◽  
Gabriel Lopez-Berestein
Keyword(s):  
Brain Tumors ◽  
Targeted Delivery ◽  
Cancer Therapeutics ◽  
Pediatric Brain Tumors ◽  
Surface Proteins ◽  
New Paradigm ◽  
Preclinical Research ◽  
Current State ◽  
Potential Therapeutic Role ◽  
Diagnostic Applications

A relatively new paradigm in cancer therapeutics is the use of cancer cell–specific aptamers, both as therapeutic agents and for targeted delivery of anticancer drugs. After the first therapeutic aptamer was described nearly 25 years ago, and the subsequent first aptamer drug approved, many efforts have been made to translate preclinical research into clinical oncology settings. Studies of aptamer-based technology have unveiled the vast potential of aptamers in therapeutic and diagnostic applications. Among pediatric solid cancers, brain tumors are the leading cause of death. Although a few aptamer-related translational studies have been performed in adult glioblastoma, the use of aptamers in pediatric neuro-oncology remains unexplored. This review will discuss the biology of aptamers, including mechanisms of targeting cell surface proteins, various modifications of aptamer structure to enhance therapeutic efficacy, the current state and challenges of aptamer use in neuro-oncology, and the potential therapeutic role of aptamers in pediatric brain tumors.

scholarly journals Development of Novel antimiRzymes for Targeted Inhibition of miR-21 Expression in Solid Cancer Cells

Molecules ◽  
2019 ◽  
Vol 24 (13) ◽  
pp. 2489 ◽  
Author(s):  
Leon M. Larcher ◽  
Tao Wang ◽  
Rakesh N. Veedu
Keyword(s):  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Targeted Delivery ◽  
Regulation Of Gene Expression ◽  
Cancer Cell Line ◽  
Cancer Therapeutics ◽  
Solid Cancer ◽  
Glioblastoma Cells

MicroRNAs (miRNAs) are short non-coding RNAs that are involved in the regulation of gene expression. Previous reports showed an over-expression of miRNA-21 (miR-21) in various cancer cells, and its up-regulation is closely related to cancer initiation, proliferation and metastasis. In this work, we envisioned the development of novel antimiRzymes (anti-miRNA-DNAzyme) that are capable of selectively targeting and cleaving miR-21 and inhibit its expression in cancer cells using the DNAzyme technique. For this purpose, we have designed different antimiRzyme candidates by systematically targeting different regions of miR-21. Our results demonstrated that RNV541, a potential arm-loop-arm type antimiRzyme, was very efficient (90%) to suppress miR-21 expression in U87MG malignant glioblastoma cell line at 200 nM concentration. In addition, RNV541 also inhibited miR-21 expression (50%) in MDA-MB-231 breast cancer cell line. For targeted delivery, we conjugated RNV541 with a transferrin receptor (TfR) targeting aptamer for TfR-mediated cancer cell delivery. As expected, the developed chimeric structure efficiently delivered the antimiRzyme RNV541 into TfR positive glioblastoma cells. TfR aptamer-RNV541 chimeric construct showed 52% inhibition of miR-21 expression in U87MG glioblastoma cells at 2000 nM concentration, without using any transfection reagents, making it a highly desirable strategy to tackle miR-21 over-expressed malignant cancers. Although these are in vitro based observations, based on our results, we firmly believe that our findings could be beneficial towards the development of targeted cancer therapeutics where conventional therapies face several challenges.

scholarly journals Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies

2020 ◽  
Vol 12 (530) ◽  
pp. eaax0876 ◽  
Author(s):  
Candice R. Gurbatri ◽  
Ioana Lia ◽  
Rosa Vincent ◽  
Courtney Coker ◽  
Samuel Castro ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Therapeutic Efficacy ◽  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
Cancer Therapeutics ◽  
Checkpoint Blockade ◽  
Genetic Circuit ◽  
Release Mechanism ◽  
Syngeneic Mouse ◽  
Syngeneic Mouse Model

Checkpoint inhibitors have revolutionized cancer therapy but only work in a subset of patients and can lead to a multitude of toxicities, suggesting the need for more targeted delivery systems. Because of their preferential colonization of tumors, microbes are a natural platform for the local delivery of cancer therapeutics. Here, we engineer a probiotic bacteria system for the controlled production and intratumoral release of nanobodies targeting programmed cell death–ligand 1 (PD-L1) and cytotoxic T lymphocyte–associated protein-4 (CTLA-4) using a stabilized lysing release mechanism. We used computational modeling coupled with experimental validation of lysis circuit dynamics to determine the optimal genetic circuit parameters for maximal therapeutic efficacy. A single injection of this engineered system demonstrated an enhanced therapeutic response compared to analogous clinically relevant antibodies, resulting in tumor regression in syngeneic mouse models. Supporting the potentiation of a systemic immune response, we observed a relative increase in activated T cells, an abscopal effect, and corresponding increases in systemic T cell memory populations in mice treated with probiotically delivered checkpoint inhibitors. Last, we leveraged the modularity of our platform to achieve enhanced therapeutic efficacy in a poorly immunogenic syngeneic mouse model through effective combinations with a probiotically produced cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF). Together, these results demonstrate that our engineered probiotic system bridges synthetic biology and immunology to improve upon checkpoint blockade delivery.

scholarly journals Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies

2019 ◽  
Author(s):  
Candice Gurbatri ◽  
Courtney Coker ◽  
Taylor E. Hinchliffe ◽  
Ioana Lia ◽  
Samuel Castro ◽  
...  
Keyword(s):  
Synthetic Biology ◽  
Targeted Delivery ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Cancer Therapeutics ◽  
Similar Efficacy ◽  
Checkpoint Blockade ◽  
Syngeneic Mouse ◽  
Syngeneic Mouse Model

ABSTRACTImmunotherapies such as checkpoint inhibitors have revolutionized cancer therapy yet lead to a multitude of immune-related adverse events, suggesting the need for more targeted delivery systems. Due to their preferential colonization of tumors and advances in engineering capabilities from synthetic biology, microbes are a natural platform for the local delivery of cancer therapeutics. Here, we present an engineered probiotic bacteria system for the controlled production and release of novel immune checkpoint targeting nanobodies from within tumors. Specifically, we engineered genetic lysis circuit variants to effectively release nanobodies and safely control bacteria populations. To maximize therapeutic efficacy of the system, we used computational modeling coupled with experimental validation of circuit dynamics and found that lower copy number variants provide optimal nanobody release. Thus, we subsequently integrated the lysis circuit operon into the genome of a probioticE. coliNissle 1917, and confirmed lysis dynamics in a syngeneic mouse model usingin vivobioluminescent imaging. Expressing a nanobody against PD-L1 in this strain demonstrated enhanced efficacy compared to a plasmid-based lysing variant, and similar efficacy to a clinically relevant monoclonal antibody against PD-L1. Expanding upon this therapeutic platform, we produced a nanobody against cytotoxic T-lymphocyte associated protein -4 (CTLA-4), which reduced growth rate or completely cleared tumors when combined with a probiotically-expressed PD-L1 nanobody in multiple syngeneic mouse models. Together, these results demonstrate that our engineered probiotic system combines innovations in synthetic biology and immunotherapy to improve upon the delivery of checkpoint inhibitors.SENTENCE SUMMARYWe designed a probiotic platform to locally deliver checkpoint blockade nanobodies to tumors using a controlled lysing mechanism for therapeutic release.

scholarly journals Securinine Targets Cancer Cells through an Irak and JNK Dependent Pathway

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3791-3791
Author(s):  
Kalpana Gupta ◽  
Gary Parizher ◽  
Marcos De Lima ◽  
David N. Wald
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Therapeutics ◽  
Mechanisms Of Action ◽  
Cell Killing ◽  
Model Systems ◽  
Cancer Drug ◽  
Wild Type ◽  
Cancer Cell Death

Abstract Securinine is a plant-derived alkaloid from the securinega plant that has been used clinically as a therapeutic for primarily neurological related diseases. We and others have previously identified securinine as a promising therapeutic candidate for Acute Myeloid Leukemia and colon cancer. In particular, securinine was found to induce the differentiation and cell death of AML cells. In addition, securinine was observed to lead to preferential killing of p53 deficient cells, a clinically beneficial strategy as only cancer cells exhibit p53 deficiency. Despite the efficacy of securinine in cell and animal model systems, the mechanisms of action of securinine in inducing cancer cell death and differentiation remain largely unknown. Here we report significant insights into the mechanisms through which securinine leads to cancer cell death. Not only are these observations important in furthering the development of securinine as a cancer therapeutic, but also as they shed light on novel mechanisms of cancer therapeutics in general. Our strategy involved a global genetic screen to identify genes required for securinine-mediated killing. We used a pooled library of shRNA to knockdown the expression of 27,000 genes in cultured cells, and then screened the population of cells for resistance to securinine-mediated death. This screen identified interleukin-1 receptor associated kinase 1 (IRAK1) as an important player in securinine-mediated cancer cell killing. IRAK1 is a kinase acting in toll-like receptor signaling, a key innate immune inflammatory pathway that ultimately activates the transcription factors AP1 and NFkB. The fact that loss of IRAK1 could protect against securinine-mediated killing was quite unexpected as NFkB activation provides a pro-survival signal. To confirm the shRNA screen, IRAK1−/− cells were utilized and reconstituted with wild-type IRAK1 or kinase-deficient IRAK1. These studies confirmed the ability of securinine to preferentially kill cells expressing wild-type IRAK. Interestingly, currently used chemotherapeutics did not exhibit a similar reduced sensitivity when tested on IRAK deficient cells demonstrating the unique mechanisms of action of securinine.As TRAF6 is an adapter protein downstream of IRAK signaling, we also demonstrated that dominant negative TRAF6 impaired securinine-mediated cell killing. To further delineate how securinine induces cell death, the two major pathways downstream of IRAK, NFkB and JNK/AP1 were investigated. We observed that both pathways were rapidly induced in cancer cells through the use of gene reporter assays (NFkB) or western blot (JNK/AP1). To assess the importance of these pathways in the cell killing effects of securinine, they were inhibited using chemical inhibitors. While blockade of NFkB had no impact upon securinine-mediated killing, inhibition of JNK dramatically impaired the ability of securinine to kill cancer cells. Overall, this study provides us with a greater mechanistic insight into a promising new therapeutic candidate and provides a framework for new pathways that can be targeted for cancer drug development. Disclosures Wald: Invenio Therapeutics: Equity Ownership.

scholarly journals Novel Delivery Systems for Checkpoint Inhibitors

Medicines ◽  
2019 ◽  
Vol 6 (3) ◽  
pp. 74 ◽  
Author(s):  
Purushottam Lamichhane ◽  
Rahul Deshmukh ◽  
Julie Brown ◽  
Silvia Jakubski ◽  
Priyanka Parajuli ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Checkpoint Inhibitors ◽  
Cancer Therapeutics ◽  
Delivery Methods ◽  
Wide Range ◽  
Anti Cancer ◽  
Clinical Tools ◽  
Immense Potential ◽  
Novel Delivery Systems ◽  
Systemic Therapies

Checkpoint inhibition (CPI) therapies have been proven to be powerful clinical tools in treating cancers. FDA approvals and ongoing clinical development of checkpoint inhibitors for treatment of various cancers highlight the immense potential of checkpoint inhibitors as anti-cancer therapeutics. The occurrence of immune-related adverse events, however, is a major hindrance to the efficacy and use of checkpoint inhibitors as systemic therapies in a wide range of patients. Hence, methods of sustained and tumor-targeted delivery of checkpoint inhibitors are likely to improve efficacy while also decreasing toxic side effects. In this review, we summarize the findings of the studies that evaluated methods of tumor-targeted delivery of checkpoint inhibitors, review their strengths and weaknesses, and discuss the outlook for therapeutic use of these delivery methods.

scholarly journals Clinical Application of Oncolytic Viruses: A Systematic Review

2020 ◽  
Vol 21 (20) ◽  
pp. 7505
Author(s):  
Mary Cook ◽  
Aman Chauhan
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Phase I ◽  
Oncolytic Virus ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Cancer Therapeutics ◽  
Oncolytic Viruses ◽  
Phase Iii ◽  
Phase Ii Trials

Leveraging the immune system to thwart cancer is not a novel strategy and has been explored via cancer vaccines and use of immunomodulators like interferons. However, it was not until the introduction of immune checkpoint inhibitors that we realized the true potential of immunotherapy in combating cancer. Oncolytic viruses are one such immunotherapeutic tool that is currently being explored in cancer therapeutics. We present the most comprehensive systematic review of all oncolytic viruses in Phase 1, 2, and 3 clinical trials published to date. We performed a systematic review of all published clinical trials indexed in PubMed that utilized oncolytic viruses. Trials were reviewed for type of oncolytic virus used, method of administration, study design, disease type, primary outcome, and relevant adverse effects. A total of 120 trials were found; 86 trials were available for our review. Included were 60 phase I trials, five phase I/II combination trials, 19 phase II trials, and two phase III clinical trials. Oncolytic viruses are feverously being evaluated in oncology with over 30 different types of oncolytic viruses being explored either as a single agent or in combination with other antitumor agents. To date, only one oncolytic virus therapy has received an FDA approval but advances in bioengineering techniques and our understanding of immunomodulation to heighten oncolytic virus replication and improve tumor kill raises optimism for its future drug development.

Combination of Oncolytic Adenoviral Therapy with Chemotherapy for Enhanced Breast Cancer Cell Killing – Virotherapy in combination with chemotherapy

2008 ◽  
Vol 68 (S 01) ◽  
Author(s):  
J Jung ◽  
A Nedeljkovic-Kurepa ◽  
B Glover ◽  
DT Curiel ◽  
RK Schmutzler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cell Killing

scholarly journals Are We Paving the Way to Dig Out of the “Pandemic Hole”? A Narrative Review on SARS-CoV-2 Vaccination: From Animal Models to Human Immunization

2021 ◽  
Vol 9 (3) ◽  
pp. 53
Author(s):  
Giuseppe Tardiolo ◽  
Pina Brianti ◽  
Daniela Sapienza ◽  
Pia dell’Utri ◽  
Viviane Di Dio ◽  
...  
Keyword(s):  
Animal Models ◽  
Viral Vector ◽  
Herd Immunity ◽  
Population Level ◽  
Narrative Review ◽  
Therapeutic Interventions ◽  
Preclinical Research ◽  
Inactivated Vaccines ◽  
Preclinical And Clinical Studies ◽  
Social Upheaval

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a new pathogen agent causing the coronavirus infectious disease (COVID-19). This novel virus originated the most challenging pandemic in this century, causing economic and social upheaval internationally. The extreme infectiousness and high mortality rates incentivized the development of vaccines to control this pandemic to prevent further morbidity and mortality. This international scenario led academic scientists, industries, and governments to work and collaborate strongly to make a portfolio of vaccines available at an unprecedented pace. Indeed, the robust collaboration between public systems and private companies led to resolutive actions for accelerating therapeutic interventions and vaccines mechanism. These strategies contributed to rapidly identifying safe and effective vaccines as quickly and efficiently as possible. Preclinical research employed animal models to develop vaccines that induce protective and long-lived immune responses. A spectrum of vaccines is worldwide under investigation in various preclinical and clinical studies to develop both individual protection and safe development of population-level herd immunity. Companies employed and developed different technological approaches for vaccines production, including inactivated vaccines, live-attenuated, non-replicating viral vector vaccines, as well as acid nucleic-based vaccines. In this view, the present narrative review provides an overview of current vaccination strategies, taking into account both preclinical studies and clinical trials in humans. Furthermore, to better understand immunization, animal models on SARS-CoV-2 pathogenesis are also briefly discussed.

scholarly journals Recent Progress in Dendritic Cell-Based Cancer Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2495
Author(s):  
Kazuhiko Matsuo ◽  
Osamu Yoshie ◽  
Kosuke Kitahata ◽  
Momo Kamei ◽  
Yuta Hara ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Targeted Delivery ◽  
Cancer Vaccines ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Host Immune Responses ◽  
Near Future ◽  
Identification And Characterization

Cancer immunotherapy aims to treat cancer by enhancing cancer-specific host immune responses. Recently, cancer immunotherapy has been attracting much attention because of the successful clinical application of immune checkpoint inhibitors targeting the CTLA-4 and PD-1/PD-L1 pathways. However, although highly effective in some patients, immune checkpoint inhibitors are beneficial only in a limited fraction of patients, possibly because of the lack of enough cancer-specific immune cells, especially CD8+ cytotoxic T-lymphocytes (CTLs), in the host. On the other hand, studies on cancer vaccines, especially DC-based ones, have made significant progress in recent years. In particular, the identification and characterization of cross-presenting DCs have greatly advanced the strategy for the development of effective DC-based vaccines. In this review, we first summarize the surface markers and functional properties of the five major DC subsets. We then describe new approaches to induce antigen-specific CTLs by targeted delivery of antigens to cross-presenting DCs. In this context, the chemokine receptor XCR1 and its ligand XCL1, being selectively expressed by cross-presenting DCs and mainly produced by activated CD8+ T cells, respectively, provide highly promising molecular tools for this purpose. In the near future, CTL-inducing DC-based cancer vaccines may provide a new breakthrough in cancer immunotherapy alone or in combination with immune checkpoint inhibitors.

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