Biotherapy of Cancer: Break the Barriers to Foster Translation oF knowledge

2008 ◽  
Vol 94 (2) ◽  
pp. 182-188 ◽  
Author(s):  
Maria Ferrantini ◽  
Claudio Lombardo ◽  
Franca Moretti ◽  
Filippo Belardelli
Keyword(s):  
Clinical Research ◽  
Clinical Development ◽  
Therapeutic Interventions ◽  
Great Promise ◽  
Biological Drugs ◽  
Clinical Cancer Research ◽  
National Network ◽  
Critical Issues ◽  
Immunotherapy Of Cancer ◽  
Italian National Institute

Biotherapy of cancer holds great promise for its potential to lead to the identification of novel, selective, and effective treatments against cancer. However, the clinical development of biopharmaceuticals and biotherapy products is hampered by several and diverse barriers. Herein, we will address some of the critical issues identified both at the national and European level as the major obstacles for the translation of knowledge into clinical applications in the field of biotherapy and immunotherapy of cancer. We will also illustrate specific initiatives undertaken both in Europe and in Italy in order to support the translational and clinical research and that are expected to have a favorable impact on the process of clinical development of novel and more effective therapeutic interventions against cancer. The contents of this article are directly referred to the event “International Clinical Trials’ Day on Biotherapy of Cancer” organized in the context of the OECI Genoa 2008, with the sponsorship of Alliance Against Cancer (ACC) and the Istituto Superiore di Sanità (ISS, the Italian National Institute of Health), and under the auspices of the European Clinical Research Infrastructures Network (ECRIN). This event sees the active participation of representatives of the ISS and of the Italian Network for Tumor Biotherapy, both involved in a project recently funded by ACC and aimed at the promotion of clinical research in the field of cancer biotherapy and immunotherapy, through the creation of a national network of clinical cancer research centers and GMP facilities dedicated to the production of biological drugs and advanced medicinal products.

Potential Interventions Against BMPR2-Related Pulmonary Hypertension

2012 ◽  
Vol 11 (1) ◽  
pp. 25-32 ◽  
Author(s):  
James West ◽  
James E. Loyd ◽  
Rizwan Hamid
Keyword(s):  
Therapeutic Interventions ◽  
Great Promise ◽  
Patient Registries ◽  
Metabolic Defects ◽  
Pulmonary Arterial ◽  
Alternative Approaches ◽  
Splicing Defects ◽  
Trafficking Defects ◽  
Molecular Bases ◽  
Near Future

For more than 60 years, researchers have sought to understand the molecular basis of idiopathic pulmonary arterial hypertension (PAH). Recognition of the heritable form of the disease led to the creation of patient registries in the 1980s and 1990s, and discovery of BMPR2 as the cause of roughly 80% of heritable PAH in 2000. With discovery of the disease gene came opportunity for intervention, with focus on 2 alternative approaches. First, it may be possible to correct the effects of BMPR2 mutation directly through interventions targeted at correction of trafficking defects, increasing expression of the unmutated allele, and correction of splicing defects. Second, therapeutic interventions are being targeted at the signaling consequences of BMPR2 mutation. In particular, therapies targeting cytoskeletal and metabolic defects caused by BMPR2 mutation are currently in trials, or will be ready for human trials in the near future. Translation of these findings into therapies is the culmination of decades of research, and holds great promise for treatment of the underlying molecular bases of disease.

scholarly journals Cancer-Associated Fibroblasts as Players in Cancer Development and Progression and Their Role in Targeted Radionuclide Imaging and Therapy

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1100
Author(s):  
Sofia Koustoulidou ◽  
Mark W. H. Hoorens ◽  
Simone U. Dalm ◽  
Shweta Mahajan ◽  
Reno Debets ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Tumour Microenvironment ◽  
Therapeutic Interventions ◽  
Great Promise ◽  
Cancer Associated Fibroblasts ◽  
Functional Heterogeneity ◽  
Radioligand Therapy ◽  
Targeted Interventions ◽  
Theranostic Applications ◽  
Complex Origin

Cancer Associated Fibroblasts (CAFs) form a major component of the tumour microenvironment, they have a complex origin and execute diverse functions in tumour development and progression. As such, CAFs constitute an attractive target for novel therapeutic interventions that will aid both diagnosis and treatment of various cancers. There are, however, a few limitations in reaching successful translation of CAF targeted interventions from bench to bedside. Several approaches targeting CAFs have been investigated so far and a few CAF-targeting tracers have successfully been developed and applied. This includes tracers targeting Fibroblast Activation Protein (FAP) on CAFs. A number of FAP-targeting tracers have shown great promise in the clinic. In this review, we summarize our current knowledge of the functional heterogeneity and biology of CAFs in cancer. Moreover, we highlight the latest developments towards theranostic applications that will help tumour characterization, radioligand therapy and staging in cancers with a distinct CAF population.

scholarly journals Systemic Delivery of mLIGHT-Armed Myxoma Virus Is Therapeutic for Later-Stage Syngeneic Murine Lung Metastatic Osteosarcoma

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 337
Author(s):  
John D. Christie ◽  
Nicole Appel ◽  
Liqiang Zhang ◽  
Kenneth Lowe ◽  
Jacquelyn Kilbourne ◽  
...  
Keyword(s):  
Lung Metastases ◽  
Ex Vivo ◽  
Tumor Burden ◽  
Myxoma Virus ◽  
Oncolytic Viruses ◽  
Systemic Delivery ◽  
Clinical Cancer Research ◽  
Critical Issues

Cancers that metastasize to the lungs represent a major challenge in both basic and clinical cancer research. Oncolytic viruses are newly emerging options but successful delivery and choice of appropriate therapeutic armings are two critical issues. Using an immunocompetent murine K7M2-luc lung metastases model, the efficacy of MYXV armed with murine LIGHT (TNFSF14/CD258) expressed under virus-specific early/late promoter was tested in an advanced later-stage disease K7M2-luc model. Results in this model show that mLIGHT-armed MYXV, delivered systemically using ex vivo pre-loaded PBMCs as carrier cells, reduced tumor burden and increased median survival time. In vitro, when comparing direct infection of K7M2-luc cancer cells with free MYXV vs. PBMC-loaded virus, vMyx-mLIGHT/PBMCs also demonstrated greater cytotoxic capacity against the K7M2 cancer cell targets. In vivo, systemically delivered vMyx-mLIGHT/PBMCs increased viral reporter transgene expression levels both in the periphery and in lung tumors compared to unarmed MYXV, in a tumor- and transgene-dependent fashion. We conclude that vMyx-mLIGHT, especially when delivered using PBMC carrier cells, represents a new potential therapeutic strategy for solid cancers that metastasize to the lung.

scholarly journals Ultrasensitive Label-Free Detection of Unamplified Multidrug-Resistance Bacteria Genes with a Bimodal Waveguide Interferometric Biosensor

Diagnostics ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 845
Author(s):  
Jesús Maldonado ◽  
Ana Belén González-Guerrero ◽  
Adrián Fernández-Gavela ◽  
Juan José González-López ◽  
Laura M. Lechuga
Keyword(s):  
Antimicrobial Resistance ◽  
Negative Impact ◽  
Multidrug Resistant ◽  
Therapeutic Interventions ◽  
Great Promise ◽  
Resistant Bacteria ◽  
Label Free ◽  
Multidrug Resistant Bacteria ◽  
Label Free Detection ◽  
Encoding Gene

Infections by multidrug-resistant bacteria are becoming a major healthcare emergence with millions of reported cases every year and an increasing incidence of deaths. An advanced diagnostic platform able to directly detect and identify antimicrobial resistance in a faster way than conventional techniques could help in the adoption of early and accurate therapeutic interventions, limiting the actual negative impact on patient outcomes. With this objective, we have developed a new biosensor methodology using an ultrasensitive nanophotonic bimodal waveguide interferometer (BiMW), which allows a rapid and direct detection, without amplification, of two prevalent and clinically relevant Gram-negative antimicrobial resistance encoding sequences: the extended-spectrum betalactamase-encoding gene blaCTX-M-15 and the carbapenemase-encoding gene blaNDM-5 We demonstrate the extreme sensitivity and specificity of our biosensor methodology for the detection of both gene sequences. Our results show that the BiMW biosensor can be employed as an ultrasensitive (attomolar level) and specific diagnostic tool for rapidly (less than 30 min) identifying drug resistance. The BiMW nanobiosensor holds great promise as a powerful tool for the control and management of healthcare-associated infections by multidrug-resistant bacteria.

scholarly journals Targeting TIGIT for Immunotherapy of Cancer: Update on Clinical Development

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1277
Author(s):  
Anand Rotte ◽  
Srikumar Sahasranaman ◽  
Nageshwar Budha
Keyword(s):  
Clinical Studies ◽  
Metastatic Cancer ◽  
Safety Data ◽  
Clinical Development ◽  
Activated T Cells ◽  
Evaluation Phase ◽  
Immunotherapy Of Cancer ◽  
Advanced Stages ◽  
Immune Checkpoint Blockers ◽  
Critical Aspects

Immune checkpoint blockers have dramatically improved the chances of survival in patients with metastatic cancer, but only a subset of the patients respond to treatment. Search for novel targets that can improve the responder rates and overcome the limitations of adverse events commonly seen with combination therapies, like PD-1 plus CTLA-4 blockade and PD-1/PD-L1 plus chemotherapy, led to the development of monoclonal antibodies blocking T-cell immunoglobulin and ITIM domain (TIGIT), a inhibitory checkpoint receptor expressed on activated T cells and NK cells. The strategy showed potential in pre-clinical and early clinical studies, and 5 molecules are now in advanced stages of evaluation (phase II and above). This review aims to provide an overview of clinical development of anti-TIGIT antibodies and describes the factors considered and thought process during early clinical development. Critical aspects that can decide the fate of clinical programs, such as origin of the antibody, Ig isotype, FCγR binding, and the dose as well as dosing schedule, are discussed along with the summary of available efficacy and safety data from clinical studies and the challenges in the development of anti-TIGIT antibodies, such as identifying patients who can benefit from therapy and getting payer coverage.

scholarly journals Critical Issues in Translational and Clinical Research for the Study of New Technologies to Enhance Bone Repair

2008 ◽  
Vol 90 (Suppl 1) ◽  
pp. 43-47 ◽  
Author(s):  
Jörg Goldhahn ◽  
Bruce Mitlak ◽  
Per Aspenberg ◽  
John A. Kanis ◽  
René Rizzoli ◽  
...  
Keyword(s):  
Clinical Research ◽  
Bone Repair ◽  
New Technologies ◽  
Critical Issues

scholarly journals Immunotherapy with Cell-Based Biological Drugs to Cure HIV-1 Infection

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 77
Author(s):  
Gabriel Siracusano ◽  
Lucia Lopalco
Keyword(s):  
Multidrug Resistant ◽  
Therapeutic Interventions ◽  
Biological Drugs ◽  
Tlr Agonists ◽  
Combined Antiretroviral Therapy ◽  
Latently Infected ◽  
Cd4 Binding Site ◽  
Escape Mutants ◽  
Infected Cells ◽  
Hiv 1

Since its discovery 35 years ago, there have been no therapeutic interventions shown to enable full HIV-1 remission. Combined antiretroviral therapy (cART) has achieved the sustained control of HIV-1 replication, however, the life-long treatment does not eradicate long-lived latently infected reservoirs and can result in multiple side effects including the development of multidrug-resistant escape mutants. Antibody-based treatments have emerged as alternative approaches for a HIV-1 cure. Here, we will review clinical advances in coreceptor-targeting antibodies, with respect to anti-CCR5 antibodies in particular, which are currently being generated to target the early stages of infection. Among the Env-specific antibodies widely accepted as relevant in cure strategies, the potential role of those targeting CD4-induced (CD4i) epitopes of the CD4-binding site (CD4bs) in eliminating HIV-1 infected cells has gained increasing interest and will be presented. Together, with approaches targeting the HIV-1 replication cycle, we will discuss the strategies aimed at boosting and modulating specific HIV-1 immune responses, highlighting the harnessing of TLR agonists for their dual role as latency reverting agents (LRAs) and immune-modulatory compounds. The synergistic combinations of different approaches have shown promising results to ultimately enable a HIV-1 cure.

scholarly journals Designing Lentiviral Vectors for Gene Therapy of Genetic Diseases

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1526
Author(s):  
Valentina Poletti ◽  
Fulvio Mavilio
Keyword(s):  
Gene Therapy ◽  
Ex Vivo ◽  
Genetic Diseases ◽  
Lentiviral Vectors ◽  
Clinical Applications ◽  
Clinical Development ◽  
Development Phase ◽  
Hematopoietic Stem ◽  
Monogenic Diseases ◽  
Immunotherapy Of Cancer

Lentiviral vectors are the most frequently used tool to stably transfer and express genes in the context of gene therapy for monogenic diseases. The vast majority of clinical applications involves an ex vivo modality whereby lentiviral vectors are used to transduce autologous somatic cells, obtained from patients and re-delivered to patients after transduction. Examples are hematopoietic stem cells used in gene therapy for hematological or neurometabolic diseases or T cells for immunotherapy of cancer. We review the design and use of lentiviral vectors in gene therapy of monogenic diseases, with a focus on controlling gene expression by transcriptional or post-transcriptional mechanisms in the context of vectors that have already entered a clinical development phase.

Beyond Human Subjects: Risk, Ethics, and Clinical Development of Nanomedicines

2012 ◽  
Vol 40 (4) ◽  
pp. 841-847 ◽  
Author(s):  
Jonathan Kimmelman
Keyword(s):  
Clinical Research ◽  
Research Ethics ◽  
Human Subjects ◽  
Clinical Development ◽  
Nuremberg Code ◽  
Human Research ◽  
Clinical Investigator ◽  
Nazi Doctors ◽  
Personal Interests

Like all policies, contemporary human research policies are the product of their history. The scandals and traumas motivating their creation — the Nazi doctors trials, Tuskegee, the Milgram experiment on obedience — however different in their particulars, all share a common narrative: a scientist, pursuing valued social ends, runs roughshod over the personal interests of disadvantaged human subjects. From the Nuremberg code through the latest revisions of the Declaration of Helsinki, research ethics policies have sought to erect a sphere of protection around the latter.As a consequence of this history, all major policies start with a well-rehearsed model of human investigations. Clinical research is viewed as an encounter between investigators and volunteers. The clinical investigator is given certain duties. The human volunteer has certain moral entitlements. What is ethically at stake in human investigations inheres in the nature and quality of the interactions between investigators and volunteers. These interactions involve an asymmetry because the investigator has privileged knowledge and influence.

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