DDRE-21. LOMUSTINE AND TARGETED-CYTOKINE THERAPY: A BENEFICIAL LIAISON FOR RECURRENT GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi78-vi79
Author(s):  
Tobias Weiss ◽  
Thomas Look ◽  
Emanuele Puca ◽  
Roberto De Luca ◽  
Teresa Hemmerle ◽  
...  
Keyword(s):  
Immune Cells ◽  
Targeted Delivery ◽  
Ex Vivo ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Tumor Stroma ◽  
Recurrent Glioblastoma ◽  
Strong Increase ◽  
Anti Tumor Activity ◽  
Ongoing Phase

Abstract Treatment options for recurrent glioblastoma are limited and except from regorafenib (potentially), no other agent has demonstrated superior activity to lomustine. Therefore, there is an urgent need for more effective treatment strategies for recurrent glioblastoma. We investigated the combination of lomustine or bevacizumab that are frequently used for recurrent glioblastoma with L19TNF (onfekafusp alfa), a systemically administered tumor-stroma targeting antibody-cytokine fusion protein that enables a targeted delivery of tumor-necrosis factor (TNF)a to the tumor. In immunocompetent orthotopic glioma mouse models, the combination of lomustine and L19TNF demonstrated the strongest anti-tumor activity, acted in synergy and cured a majority of tumor-bearing mice, whereas lomustine or L19TNF monotherapy only had only very limited anti-tumor activity. Ex vivo profiling of the tumors and tumor-infiltrating immune cells from immunocompetent or immunodeficient hosts demonstrated immune-dependent cytotoxic and cytostatic effects on the glioma cells, and a strong increase of tumor-infiltrating immune cells upon combination therapy in immunocompetent models. Based on these encouraging results, we translate this combinatorial therapy to patients with recurrent glioblastoma. For the first patients, the treatment with lomustine and L19TNF was well tolerated and led to stable disease with a reduction in tumor perfusion. More patients are recruited in an ongoing phase I/II clinical trial with lomustine and L19TNF for patients with recurrent glioblastoma (NCT04573192).

scholarly journals A human antibody selective for transthyretin amyloid removes cardiac amyloid through phagocytic immune cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Aubin Michalon ◽  
Andreas Hagenbuch ◽  
Christian Huy ◽  
Evita Varela ◽  
Benoit Combaluzier ◽  
...  
Keyword(s):  
Immune Cells ◽  
Ex Vivo ◽  
Phase 1 ◽  
Hereditary Disease ◽  
Elderly Subjects ◽  
Human Antibody ◽  
Cardiac Amyloid ◽  
Healthy Elderly ◽  
Ongoing Phase

AbstractTransthyretin amyloid (ATTR) cardiomyopathy is a debilitating disease leading to heart failure and death. It is characterized by the deposition of extracellular ATTR fibrils in the myocardium. Reducing myocardial ATTR load is a therapeutic goal anticipated to translate into restored cardiac function and improved patient survival. For this purpose, we developed the selective anti-ATTR antibody NI301A, a recombinant human monoclonal immunoglobulin G1. NI301A was cloned following comprehensive analyses of memory B cell repertoires derived from healthy elderly subjects. NI301A binds selectively with high affinity to the disease-associated ATTR aggregates of either wild-type or variant ATTR related to sporadic or hereditary disease, respectively. It does not bind physiological transthyretin. NI301A removes ATTR deposits ex vivo from patient-derived myocardium by macrophages, as well as in vivo from mice grafted with patient-derived ATTR fibrils in a dose- and time-dependent fashion. The biological activity of ATTR removal involves antibody-mediated activation of phagocytic immune cells including macrophages. These data support the evaluation of safety and tolerability of NI301A in an ongoing phase 1 clinical trial in patients with ATTR cardiomyopathy.

scholarly journals Biomarkers in Pancreatic Cancer as Analytic Targets for Nanomediated Imaging and Therapy

Materials ◽  
2021 ◽  
Vol 14 (11) ◽  
pp. 3083
Author(s):  
Cristiana Maria Grapa ◽  
Lucian Mocan ◽  
Dana Crisan ◽  
Mira Florea ◽  
Teodora Mocan
Keyword(s):  
Drug Delivery ◽  
Pancreatic Cancer ◽  
Targeted Delivery ◽  
Drug Toxicity ◽  
Treatment Options ◽  
Tumor Stroma ◽  
Chemotherapy Response ◽  
Rising Incidence ◽  
Tumor Accumulation ◽  
Accumulation Ability

As the increase in therapeutic and imaging technologies is swiftly improving survival chances for cancer patients, pancreatic cancer (PC) still has a grim prognosis and a rising incidence. Practically everything distinguishing for this type of malignancy makes it challenging to treat: no approved method for early detection, extended asymptomatic state, limited treatment options, poor chemotherapy response and dense tumor stroma that impedes drug delivery. We provide a narrative review of our main findings in the field of nanoparticle directed treatment for PC, with a focus on biomarker targeted delivery. By reducing drug toxicity, increasing their tumor accumulation, ability to modulate tumor microenvironment and even improve imaging contrast, it seems that nanotechnology may one day give hope for better outcome in pancreatic cancer. Further conjugating nanoparticles with biomarkers that are overexpressed amplifies the benefits mentioned, with potential increase in survival and treatment response.

scholarly journals Type-1 IFN primed monocytes in pathogenesis of idiopathic pulmonary fibrosis

2020 ◽  
Author(s):  
Emily Fraser ◽  
Laura Denney ◽  
Karl Blirando ◽  
Chaitanya Vuppusetty ◽  
Agne Antanaviciute ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Immune Cells ◽  
Therapeutic Target ◽  
Lung Fibrosis ◽  
Ex Vivo ◽  
Treatment Options ◽  
Gene Expression Signature ◽  
Severe Form

ABSTRACTIdiopathic pulmonary fibrosis (IPF) is the most severe form of lung fibrosis. It is progressive, and has an extremely poor outcome and limited treatment options. The disease exclusively affects the lungs, and thus less attention has been focused on blood-borne immune cells. which could be a more effective therapeutic target than lung-based cells. Here, we questioned if circulating monocytes, which has been shown to be increased in IPF, bore abnormalities that might contribute to its pathogenesis. We found that levels of circulating monocytes correlated directly with the extent of fibrosis in the lungs, and increased further during acute clinical deterioration. Monocytes in IPF were phenotypically distinct, displaying increased expression of CD64, a type 1 IFN gene expression signature and a greater magnitude of type 1 IFN response when stimulated. These abnormalities were accompanied by markedly raised CSF-1 levels in the serum, prolonged survival of monocytes ex vivo, and increased numbers of monocytes in lung tissue. Our study defines the key monocytic abnormalities in IPF, proposing type 1 IFN-primed monocytes as a potential driver of an aberrant repair response and fibrosis. It provides a rationale for targeting monocytes and identifies monocytic CD64 as a potential specific therapeutic target for IPF.

scholarly journals A human ex vivo coculture model to investigate peritoneal metastasis and innovative treatment options

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Dina Mönch ◽  
Jana Koch ◽  
Annika Maaß ◽  
Nicole Janssen ◽  
Thomas Mürdter ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Peritoneal Metastasis ◽  
Ex Vivo ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Average Survival ◽  
Extracellular Matrix Components ◽  
Coculture Model ◽  
New Treatment

Abstract Objectives Peritoneal metastasis (PM) is commonly observed in patients with colorectal cancer (CRC). The outcome of these patients is poor, with an average survival of only six months without therapy, which requires a better understanding of PM biology and new treatment strategies. Methods We established and characterized a human ex vivo peritoneal model to investigate the mechanisms of peritoneal seeding and possible treatment options. For this, CRC cell lines and patient-derived tumor organoids were cultured together with human peritoneum to investigate the invasion of malignant cells and the effects of local chemotherapy. Results Fresh human peritoneum was cultured for up to three weeks in a stainless steel ring system, allowing for survival of all peritoneal structures. Peritoneal cell survival was documented by light microscopy and immunohistochemical staining. Further, immunohistological characterization of the tissue revealed CD3-positive T-lymphocytes and vimentin-positive fibroblasts within the peritoneum. In addition, extracellular matrix components (collagens, matrix metalloproteinases) were localized within the tissue. Coculture with CRC cell lines and patient-derived CRC organoids revealed that cancer cells grew on the peritoneum and migrated into the tissue. Coculture with CRC cells confirmed that hyperthermal treatment at 41 °C for 90 min significantly enhanced the intracellular entry of doxorubicin. Moreover, treatment with mitomycin C under hyperthermic conditions significantly reduced the amount of cancer cells within the peritoneum. Conclusions This human ex vivo peritoneal model provides a stringent and clinically relevant platform for the investigation of PM and for further elucidation of possible treatment options.

scholarly journals Role of NK Cells in Cancer and Immunotherapy

Onco ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 158-175
Author(s):  
Paresh Vishwasrao ◽  
Susanta K. Hui ◽  
D. Lynne Smith ◽  
Vishal Khairnar
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Immune Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Treatment Options ◽  
Oncology Research ◽  
Cell Immunotherapy ◽  
Car T ◽  
Knowledge Of Cancer

Increasing knowledge of cancer immunology has led to the design of therapies using immune cells directly or manipulating their activity, collectively termed immunotherapy. In the field of immuno-oncology, research on adaptive immune T cells has led to the development of CAR-T cells. Innate immune cells such as NK cells can also eliminate oncogenically transformed cells and regulate cells of the immune system. Considering NK cells as a live drug, numerous methods for the isolation and activation of NK cells have been shown to be clinically and therapeutically relevant. In such processes, various cytokines and antibodies present a source of stimulation of NK cells and enhance the efficacy of such treatments. The ex vivo expansion and activation of NK cells, along with genetic modification with CAR, enhance their antitumor activity. Recent preclinical studies have shown an antitumor effect through extracellular vesicles (EVs) derived from NK cells. Work with autologous NK cells has provided insights for clinical applications. In this review, we outline the recent advances of NK-cell-based immunotherapies, summarizing CAR-NK cells, BiKEs, and TriKEs as treatment options against cancer. This review also discusses the challenges of NK cell immunotherapy.

scholarly journals Systematic Review and network meta-analysis of the efficacy of existing treatments for patients with recurrent glioblastoma (rGBM)

2021 ◽  
Author(s):  
Anna Schritz ◽  
Nassera Aouali ◽  
Aurélie Fischer ◽  
Coralie Dessenne ◽  
Roisin Adams ◽  
...  
Keyword(s):  
Systematic Review ◽  
Meta Analysis ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Comprehensive Overview ◽  
Free Survival ◽  
Treatment Regimens ◽  
Poor Outcomes

Abstract Background Despite advances in the treatment of cancers over the last years, treatment options for patients with recurrent glioblastoma (rGBM) remain limited with poor outcomes. Many regimens have been investigated in clinical trials; however, there is a lack of knowledge on comparative effectiveness. The aim of this systematic review is to provide an overview of existing treatment strategies and to estimate the relative efficacy of these regimens in terms of progression free survival (PFS) and overall survival (OS). Methods We conducted a systematic review to identify randomized controlled trials (RCTs) investigating any treatment regimen in adult patients suffering from rGBM. Connected studies reporting at least one of our primary outcomes were included in a Bayesian network meta-analysis (NMA) estimating relative treatment effects. Results Forty RCTs fulfilled our inclusion criteria evaluating the efficacy of thirty-eight drugs as mono- or combination therapy. Median OS ranged from 2.9 to 18.3 months; median PFS ranged from 0.7 to 6 months. We performed an NMA including 24 treatments that were connected within a large evidence network. Our NMA indicated improvement in PFS with most bevacizumab (BV) based regimens compared to other regimens. We did not find any differences in OS between treatments. Conclusion This systematic review provides a comprehensive overview of existing treatment options for rGBM. The NMA provides relative effects for many of these treatment regimens, which have not been directly compared in RCTs. Overall, outcomes for patients with rGBM remain poor across all treatment options, highlighting the need for innovative treatment options.

scholarly journals New Mechanistic Insights, Novel Treatment Paradigms, and Clinical Progress in Cerebrovascular Diseases

2021 ◽  
Vol 13 ◽  
Author(s):  
Johannes Boltze ◽  
Jaroslaw A. Aronowski ◽  
Jerome Badaut ◽  
Marion S. Buckwalter ◽  
Mateo Caleo ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Targeted Delivery ◽  
Basic Science ◽  
Science Studies ◽  
Treatment Options ◽  
Experimental Studies ◽  
Treatment Strategies ◽  
Cerebrovascular Diseases ◽  
Stroke Recovery ◽  
Novel Treatment

The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress.

Targeting glioblastoma with novel immunocytokines.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2558-2558
Author(s):  
Patrick Roth ◽  
Tobias Weiss ◽  
Emanuele Puca ◽  
Manuela Silginer ◽  
Teresa Hemmerle ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Fusion Protein ◽  
Inflammatory Cytokines ◽  
Targeted Delivery ◽  
Treatment Options ◽  
Blood Perfusion ◽  
Recurrent Glioblastoma ◽  
Who Grade ◽  
Novel Treatment ◽  
Pro Inflammatory Cytokines

2558 Background: There is an urgent need for novel treatment options for patients with glioblastoma, the most frequent malignant primary brain tumor. In contrast to other types of cancer, immunotherapeutic approaches have so far not been successful against glioblastoma. Converting the glioma microenvironment from a "cold" and immunosuppressive status into a more "hot" and immunopermissive phenotype may allow for clinically meaningful anti-tumor immune responses. Methods: We explored the activity of novel immunocytokines based on the L19 antibody, specific to a tumor-associated epitope of extracellular fibronectin, for the targeted delivery of three pro-inflammatory cytokines (IL-2, IL-12, TNF) to the microenvironment of gliomas. Following an extensive preclinical assessment in 2 orthotopic immunocompetent mouse glioma models, we used a fully-human L19-hTNF fusion protein to treat human patients with recurrent glioblastoma. Results: Intravenous administration of L19-mIL12 or L19-mTNF prolonged survival and cured a proportion of tumor-bearing mice while no effect was seen with L19-IL2. When L19-mIL12 or L19-mTNF were administered to glioma-bearing RAG−/− mice, no therapeutic activity was observed which suggests adaptive immunity as an underlying mechanism. On a mechanistic level, both immunocytokines induced the infiltration of the tumor site with lymphocytes and promoted the expression of pro-inflammatory cytokines in the tumor microenvironment. In addition, L19-mTNF induced tumor necrosis. Based on these preclinical findings, we initiated a phase I/II clinical trial with a fully-human L19-hTNF fusion protein for patients with isocitrate dehydrogenase (IDH1R132H) wildtype WHO Grade III or IV glioma at first relapse (NCT03779230). Treatment was safe and well tolerated in the first three glioblastoma patients. Administration of L19-hTNF resulted in reduced regional blood perfusion in the tumor region and was associated with more necrotic areas within the tumor as well as an increased number of tumor-infiltrating CD4 and CD8 T cells. Conclusions: The data obtained with the comprehensive preclinical characterization and subsequent clinical translation form the basis for future studies with immunocytokines as novel treatment option for patients with malignant brain tumors. Clinical trial information: NCT03779230 .

scholarly journals P13.07 Multi-omics as a tool for elucidating temozolomide resistance in glioblastoma multiforme

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii63-iii63
Author(s):  
F Fabro ◽  
E Tóth ◽  
L J M Dekker ◽  
T M Luider ◽  
T M Pierson ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Treatment Options ◽  
Tumor Resection ◽  
Treatment Strategies ◽  
Recurrent Glioblastoma ◽  
Biological Information ◽  
Patient Specific ◽  
Complex Nature ◽  
Current Standard ◽  
Medical Software

Abstract BACKGROUND Glioblastoma multiforme is the most common and aggressive brain tumor in adults, with an average overall survival of 14 months. Current standard of care consists of tumor resection followed by radiotherapy with concomitant temozolomide and adjuvant temozolomide. However, glioblastoma recurs in all patients. The causes reside in the enhanced invasiveness and resistance to treatment, giving a clear indication that recurrent and resistant glioblastoma biology must be understood better in order to achieve future treatment strategies to benefit the patients. The complex nature of recurrent glioblastoma makes its understanding still a challenging achievement in the field. Nowadays multi-omics approaching is developing further and further and it may be used to unravel, by combining different layers of biological information, a comprehensive view of the changes occurring during the treatment. MATERIAL AND METHODS A discovery set of 13 primary patient-derived glioblastoma stem-like cultures were analysed, comprising selected resistant, induced resistant and with pre-existing resistance conditions. A characterization of transcriptome, proteome and phosphoproteome was performed using RNAseq and liquid chromatography mass spectrometry. Additional 10 paired primary and recurrent tumor tissues were utilized as a validation set. The data obtained was visualised, explored and integrated through TIBCO Spotfire, Ingenuity Pathway Analysis, STRING and COREMINE medical software. RESULTS Genetic regulatory processes such as DNA repair mechanism, mRNA splicing and chromatin assembly were shown to be common over-represented trends in resistant and recurrent glioblastomas as a result of increased genomic instability and stress deriving from acute an repeated temozolomide exposure. Due to the immense heterogeneity of glioblastomas, other proteins and genes here identified as differentially expressed need a further investigation as they also may play an important role in relevant biological processes in a patient-specific way. CONCLUSION This study provides further understanding of glioblastoma biology revealing an association with processes of recurrence and temozolomide resistance, moreover offering potential therapeutic targets for better treatment options for glioblastoma patients.

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