Immunocompetent Mouse Models in the Search for Effective Immunotherapy in Glioblastoma

Glioblastoma (GBM) is the most aggressive intrinsic brain tumor in adults. Despite maximal therapy consisting of surgery and radio/chemotherapy, GBM remains largely incurable with a median survival of less than 15 months. GBM has a strong immunosuppressive nature with a multitude of tumor and microenvironment (TME) derived factors that prohibit an effective immune response. To date, all clinical trials failed to provide lasting clinical efficacy, despite the relatively high success rates of preclinical studies to show effectivity of immunotherapy. Various factors may explain this discrepancy, including the inability of a single mouse model to fully recapitulate the complexity and heterogeneity of GBM. It is therefore critical to understand the features and limitations of each model, which should probably be combined to grab the full spectrum of the disease. In this review, we summarize the available knowledge concerning immune composition, stem cell characteristics and response to standard-of-care and immunotherapeutics for the most commonly available immunocompetent mouse models of GBM.

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Abstract PO056: The kinetics of the anti-glioblastoma immune response in immunocompetent mouse models is influenced by neglected factors

10.1158/2326-6074.tumimm20-po056 ◽

2021 ◽

Author(s):

Breanna R. Noffsinger ◽

Alexandra Witter ◽

Natasha Shebani ◽

Aizhen Xiao ◽

Qing Zhong ◽

...

Keyword(s):

Immune Response ◽

Mouse Models ◽

Immunocompetent Mouse ◽

Kinetics Of

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Active DNA Aβ42 vaccination as immunotherapy for Alzheimer disease

Translational Neuroscience ◽

10.2478/s13380-012-0037-6 ◽

2012 ◽

Vol 3 (4) ◽

Cited By ~ 14

Author(s):

Doris Lambracht-Washington ◽

Roger Rosenberg

Keyword(s):

Immune Response ◽

Clinical Trials ◽

Alzheimer Disease ◽

Mouse Models ◽

Treatment Option ◽

Neurodegenerative Disorder ◽

Autoimmune Encephalitis ◽

Active Immunization ◽

The Brain ◽

Additional Safety

AbstractAs a neurodegenerative disorder, Alzheimer disease (AD) is the most common form of dementia found in the aging population. Immunotherapy with passive or active immunizations targeting amyloid beta (Aβ) build-up in the brain may provide a possible treatment option and may help prevent AD from progressing. A number of passive immunizations with anti-Aβ42 antibodies are in different phases of clinical trials. One active immunization approach, AN-1792, was stopped after the development of autoimmune encephalitis in 6% of patients and a second one, CAD106, in which a small Aβ epitope is used, is currently in safety and tolerability studies. Besides active immunizations with proteins or peptides, active immunizations using DNA which codes for the protein against which the immune response will be directed, so called genetic immunizations, provide additional safety as the immune response in DNA immunizations differs quantitatively and qualitatively from the response elicited by peptide immunizations. We summarize in this review our data using DNA Aβ42 immunizations in mouse models and discuss the results together with the results presented by many other groups working on a DNA vaccine as treatment option for AD.

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Faculty Opinions recommendation of Post-traumatic osteoarthritis: from mouse models to clinical trials.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718020232.793478691 ◽

2013 ◽

Author(s):

Virginia Kraus

Keyword(s):

Clinical Trials ◽

Mouse Models ◽

Post Traumatic

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Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

Advances in Pulmonary Hypertension ◽

10.21693/1933-088x-9.4.214 ◽

2010 ◽

Vol 9 (4) ◽

pp. 214-219

Author(s):

Robyn J. Barst

Keyword(s):

Clinical Trials ◽

Pulmonary Arterial Hypertension ◽

Drug Development ◽

Phase 1 ◽

Preclinical Studies ◽

Phase 2 ◽

Phase 3 ◽

Preclinical Testing ◽

New Drug ◽

Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

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Co-Clinical Trials: An Innovative Drug Development Platform for Cholangiocarcinoma

Pharmaceuticals ◽

10.3390/ph14010051 ◽

2021 ◽

Vol 14 (1) ◽

pp. 51

Author(s):

Brinda Balasubramanian ◽

Simran Venkatraman ◽

Kyaw Zwar Myint ◽

Tavan Janvilisri ◽

Kanokpan Wongprasert ◽

...

Keyword(s):

Clinical Trials ◽

Targeted Therapy ◽

Drug Development ◽

Surgical Resection ◽

Treatment Options ◽

Standard Of Care ◽

Time Data ◽

Current Standard ◽

Innovative Drug ◽

Curative Intent

Cholangiocarcinoma (CCA), a group of malignancies that originate from the biliary tract, is associated with a high mortality rate and a concerning increase in worldwide incidence. In Thailand, where the incidence of CCA is the highest, the socioeconomic burden is severe. Yet, treatment options are limited, with surgical resection being the only form of treatment with curative intent. The current standard-of-care remains adjuvant and palliative chemotherapy which is ineffective in most patients. The overall survival rate is dismal, even after surgical resection and the tumor heterogeneity further complicates treatment. Together, this makes CCA a significant burden in Southeast Asia. For effective management of CCA, treatment must be tailored to each patient, individually, for which an assortment of targeted therapies must be available. Despite the increasing numbers of clinical studies in CCA, targeted therapy drugs rarely get approved for clinical use. In this review, we discuss the shortcomings of the conventional clinical trial process and propose the implementation of a novel concept, co-clinical trials to expedite drug development for CCA patients. In co-clinical trials, the preclinical studies and clinical trials are conducted simultaneously, thus enabling real-time data integration to accurately stratify and customize treatment for patients, individually. Hence, co-clinical trials are expected to improve the outcomes of clinical trials and consequently, encourage the approval of targeted therapy drugs. The increased availability of targeted therapy drugs for treatment is expected to facilitate the application of precision medicine in CCA.

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Heterologous vaccination regimens with self-amplifying RNA and adenoviral COVID vaccines induce robust immune responses in mice

Nature Communications ◽

10.1038/s41467-021-23173-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Alexandra J. Spencer ◽

Paul F. McKay ◽

Sandra Belij-Rammerstorfer ◽

Marta Ulaszewska ◽

Cameron D. Bissett ◽

...

Keyword(s):

Immune Response ◽

Clinical Trials ◽

T Cells ◽

Immune Responses ◽

Viral Vectors ◽

Cytotoxic T Cells ◽

Antibody Responses ◽

Limited Data ◽

Vectored Vaccine ◽

Cellular Immune

AbstractSeveral vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two-dose heterologous vaccination regimens than single-dose regimens. Neutralising titres after heterologous prime-boost were at least comparable or higher than the titres measured after homologous prime boost vaccination with viral vectors. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1+ CD4 T cells, which is superior to the response induced in homologous vaccination regimens in mice. These results underpin the need for clinical trials to investigate the immunogenicity of heterologous regimens with alternate vaccine technologies.

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Rationalisations for women-only randomised controlled trials in conditions that affect both sexes: a scoping review protocol

BMJ Open ◽

10.1136/bmjopen-2020-043370 ◽

2021 ◽

Vol 11 (2) ◽

pp. e043370

Author(s):

Ainsley Matthewson ◽

Olena Bereznyakova ◽

Brian Dewar ◽

Alexandra Davis ◽

Mark Fedyk ◽

...

Keyword(s):

Clinical Trials ◽

Scoping Review ◽

Randomised Controlled Trials ◽

Standard Of Care ◽

Standards Of Care ◽

Controlled Trials ◽

Theory Approach ◽

Reference Centre ◽

Cochrane Database ◽

Randomised Controlled

IntroductionWomen have historically been under-represented in randomised controlled trials (RCTs), including many landmark RCTs that established standards of care. In light of this fact, some modern researchers are calling for replication of earlier landmark trials with women only. This approach is ethically concerning, in that it would require some enrolled women to be deprived of treatments that are currently considered standard of care.ObjectiveIn an attempt to better understand the justification of a women-only approach to designing clinical trials, this study looks to systematically categorise the number of women-only RCTs for conditions that affect both men and women and the reasons given within the medical and philosophical literatures to perform them.MethodologyThis scoping review of the literature will search, screen and select articles based on predetermined inclusion/exclusion criteria, after which a grounded theory approach will be used to synthesise the data. It is expected that there will be a variety of reasons given for why a women-only trial may be justified. Electronic databases that will be searched include MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Clinical Trials Register, Web of Science Proceedings, ClinicalTrials.gov, Philosopher’s Index, Phil Papers, JSTOR, Periodicals Archive Online, Project MUSE and the National Reference Centre for Bioethics.SignificanceThe scope of this study is to determine published rationales used to justify women-only randomised trials, both in the case of new trials and in the repetition of landmark trials.Ethics and disseminationResearch ethics board approval is not required for this study as there is no participant involvement. Results will be published as a stand-alone manuscript and will inform a larger project related to the ethics of a women-only RCT of carotid intervention for women with symptomatic high-grade carotid stenosis.

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Macrophage Activation and Cytokine Release Syndrome in COVID-19: Current Updates and Analysis of Repurposed and Investigational Anti-Cytokine Drugs

Drug Research ◽

10.1055/a-1291-7692 ◽

2021 ◽

Cited By ~ 1

Author(s):

Ashif Iqubal ◽

Farazul Hoda ◽

Abul Kalam Najmi ◽

Syed Ehtaishamul Haque

Keyword(s):

Immune Response ◽

Clinical Trials ◽

Macrophage Activation ◽

Fatality Rate ◽

Cytokine Storm ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Disease Condition ◽

Inflammatory Drugs ◽

Anti Inflammatory

AbstractCoronavirus disease (COVID-19) emerged from Wuhan, has now become pandemic and the mortality rate is growing exponentially. Clinical complication and fatality rate is much higher for patients having co-morbid issues. Compromised immune response and hyper inflammation is hall mark of pathogenesis and major cause of mortality. Cytokine release syndrome (CRS) or cytokine storm is a term used to affiliate the situation of hyper inflammation and therefore use of anti-cytokine and anti-inflammatory drugs is used to take care of this situation. Looking into the clinical benefit of these anti-inflammatory drugs, many of them enter into clinical trials. However, understanding the immunopathology of COVID-19 is important otherwise, indiscriminate use of these drugs could be fetal as there exists a very fine line of difference between viral clearing cytokines and inflammatory cytokines. If any drug suppresses the viral clearing cytokines, it will worsen the situation and hence, the use of these drugs must be based on the clinical condition, viral load, co-existing disease condition and severity of the infection.

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Stereotactic cisternal lavage in patients with aneurysmal subarachnoid hemorrhage with urokinase and nimodipine for the prevention of secondary brain injury (SPLASH): study protocol for a randomized controlled trial

Trials ◽

10.1186/s13063-021-05208-6 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Roland Roelz ◽

Fabian Schubach ◽

Volker A. Coenen ◽

Carolin Jenkner ◽

Christian Scheiwe ◽

...

Keyword(s):

Clinical Trials ◽

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Neurological Outcome ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Standard Of Care ◽

Secondary Brain Injury ◽

Ringer’S Solution ◽

Randomized Controlled ◽

Therapy Protocol

Abstract Background Delayed cerebral infarction (DCI) is a major cause of death and poor neurological outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). Direct intrathecal therapies with fibrinolytic and spasmolytic drugs have appeared promising in clinical trials. However, access to the subarachnoid space for intrathecal drug administration is an unsolved problem so far, especially in patients with endovascular aneurysm securing. We investigate a therapy protocol based on stereotactic catheter ventriculocisternostomy (STX-VCS), a new approach to overcome this problem. The primary objective of this study is to assess whether cisternal lavage with urokinase, nimodipine, and Ringer’s solution administered via a stereotactically implanted catheter into the basal cisterns (= investigational treatment (IT)) is safe and improves neurological outcome in patients with aSAH. Methods This is a randomized, controlled, parallel-group, open-label phase II trial. Fifty-four patients with severe aSAH (WFNS grade ≥ 3) will be enrolled at one academic tertiary care center in Southern Germany. Patients will be randomized at a ratio of 1:1 to receive either standard of care only or standard of care plus the IT. The primary endpoint is the proportion of subjects with a favorable outcome on the Modified Rankin Scale (defined as mRS 0–3) at 6 months after aSAH. Further clinical and surrogate outcome parameters are defined as secondary endpoints. Discussion New approaches for the prevention and therapy of secondary brain injury in patients with aSAH are urgently needed. We propose this RCT to assess the clinical safety and efficacy of a novel therapy protocol for intrathecal administration of urokinase, nimodipine, and Ringer’s solution. Trial registration Deutsches Register Klinischer Studien (German Clinical Trials Register), DRKS00015645. Registered on 8 May 2019

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