Neoplasms

All Conditions

Rare Diseases

Glioblastoma

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Multidisciplinary and innovative approach based on plasma markers of inflammation (cytokines, circulating RNA, and extracellular microvesicles), and multimodal imaging using 18F-GE-180 positron emission tomography (PET) and advanced MRI techniques,

PET examination of glioblastoma using 18F-GE-180 PET radio-metabolic marker

18F-GE-180 PET

MRI examination using advanced sequences to characterize tumor microstructure and function

Advanced MRI

Hematopoietic stem cells will be collected by the aspiration of bone marrow during the surgical intervention for tumor resection

Collection of hematopoietic stem cells

blood withdrawal for evaluation of plasma biomarkers of inflammation, circulating microvesicles, and RNA

Blood withdrawal

Glioblastoma stem cells (GSCs) will be isolated from the tumor

Collection of Cancer Stem Cells

Letterio S Politi, MD

Luca A Cappellini, MD

The goal of this interventional study is the development and validation of imaging markers, MRI and PET, plasma biomarkers, and/or cell markers that could support clinicians and researchers in differentiating pseudoprogression from true tumor progression in routine clinical activities and clinical trials in patients affected by glioblastoma.

The endpoints of the study are:

* the elaboration of predictive models using imaging advanced biomarkers, PET and MRI, biological serum markers, and cancer cell derived makers to differentiate tumor pseudoprogression or real progression in patients affected by glioblastoma who underwent therapeutical protocol as per treating physicians' indications (Stupp or hypofractionated RT)
* to establish an in vivo murine model of pseudoprogression by orthotopic transplantation of glioblastoma stem cells derived from thirty-five patient subjected to subsequent treatment with irradiation and temozolomide administration.

Participants will undergo:

* baseline MRI and 18F-GE-180 PET imaging, and blood withdrawal
* surgery
* collection of glioblastoma stem cells (and hematopoietic stem cells from a sub-group of subjects)
* standard treatment with radiotherapy and chemotherapy
* MRI every 3 months
* PET and blood withdrawal in case of MRI evidence of either suspected tumor progression or pseudoprogression
* second surgery OR stereotactic biopsy OR clinico-radiological follow-up as for standard of care according to the Institutional Multidisciplinary Brain Tumor Board

Rationale

Glioblastoma (GBM) is the most common malignant primary tumor of the central nervous system characterized by an extremely severe prognosis with a median survival of 14-16 months from diagnosis. Patients affected by high-grade gliomas are treated with a combination of radiotherapy and temozolomide chemotherapy. To date, the efficacy of the treatment is assessed through MRI which shows evidence of early radiological progression in up to 50% of all patients. Importantly, signs of tumor progression on MRI images may actually represent pseudoprogression in up to 64% of cases meaning that within 6 months from the end of the radiation treatment 20-30% of patients show increased contrast enhancement that resolves on subsequent MRI scans without changes in the treatment. Pseudoprogression is a phenomenon likely related to inflammation and disruption of the blood-brain barrier (BBB) caused by radiation and by the concurrent temozolomide treatment. Being a self-resolving consequence of the therapy rather than a sign of tumor growth, mistaking pseudoprogression for real progression leads to premature discontinuation of therapy and inappropriate evaluation of progression free survival and response rate in clinical trials impairing clinical practice.

Therefore, the differentiation of pseudoprogression from true progression is both a challenge in everyday clinical activity and a relevant problem in clinical trials and research.

A major limitation to the development and assessment of efficacy of current and new therapies in the setting of brain tumors, both at preclinical and clinical levels, however, is the lack of reliable trial endpoints.

A combination of advanced imaging methods, MRI and PET, with innovative techniques investigating cancer-specific biology will allow a holistic characterization of the tumor from multiple aspects crucial to enable a personalized diagnostic and therapeutical approach.

Objective

The main goal of the project is the development and validation of imaging markers, MRI and PET, plasma biomarkers, and/or cell markers that could support clinicians and researchers in differentiating pseudoprogression from true tumor progression in routine clinical activities and clinical trials in patients affected by GBM.

Main trial endpoints

The primary endpoint of the study is the elaboration of predictive models (evaluation of specificity and sensitivity) using imaging advanced biomarkers, PET and MRI, biological serum markers, and cancer cell derived makers to differentiate tumor pseudoprogression or real progression in patients affected by GBM who underwent therapeutical protocol as per treating physicians' indications (Stupp or hypofractionated RT).

Secondary trial endpoints

We aim to establish an in vivo murine model of pseudoprogression by orthotopic transplantation of GSCs derived from thirty-five patient subjected to subsequent treatment with irradiation and temozolomide administration.

Trial design

This is a pilot prospective interventional clinical trial using a novel 18F-GE-180 PET radio-metabolic marker (AxMP) and MRI with advanced sequences with no modification of standard of care treatment and additional diagnostic procedures that do not pose more than minimal additional risk or burden to the subjects compared to normal clinical practice. The trial will enroll 75 patients in 42 months and will be concluded in 60 months.

Trial population

The trial will prospectively enroll 75 patients affected by isocitrate dehydrogenase gene (IDH)-wild type Glioblastoma, with an age above 18 years old , who will undergo standard of care treatment.

Interventions

Before surgery and starting the standard treatment with RT and chemotherapy, all subjects will undergo baseline MRI and 18F-GE-180 PET imaging, and blood withdrawal for evaluation of plasma biomarkers of inflammation, circulating microvesicles, and RNA. MRI exams will then be performed as per standard practice of care every 3 months and in case of clinical deterioration suggesting possible disease recurrence/progression. A second PET-scan along with plasma sample collection will be performed only in case of MRI evidence of either suspected tumor progression or pseudoprogression. In case of MRI evidence of an increase in tumor size (either suspected true tumor progression or pseudoprogression), as for standard of care, the Institutional Multidisciplinary Brain Tumor Board (composed of neurosurgeons, neuro-oncologists, neuroradiologists, radiotherapists) will discuss each patient for determining clinical indication and feasibility of second surgery. In those patients in whom second surgery is not indicated, a stereotactic biopsy will be considered if feasible, safe, and clinically useful. If a stereotactic biopsy is not feasible and safe, a 3-month follow-up will be planned before a change in treatment. When available, pathology will be considered as the gold standard for differentiation pseudoprogression from true tumor progression. In all other subjects, follow-up and overall survival data will be evaluated for this differentiation. In all the subjects, overall survival data will be also recorded for statistical analyses.

Cancer Stem Cells /CSC) will be collected form 35 patients and Hematopoietic Stem Cells (HSC) from 10 patients for the creation of a vitro and in vivo murine model.

Ethical considerations relating to the clinical trial including the expected benefit to the individual subject or group of patients represented by the trial subjects as well as the nature and extent of burden and risks This trial will be conducted in compliance with the protocol, the current version of the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice guideline as well as international and national legal and regulatory requirements.

All study participants will receive the standards of care for GBM. The additional diagnostic procedures (PET scan with a novel tracer and high resolution 3 Tesla scanner MRI) do not entail specific risks for the patient. At every time point (at least before surgery, before RT and in case of pseudoprogression) additional blood samples for the determinations of markers of inflammation and the isolation of circulating microvesicles and RNA will be collected from the patients. Glioblastoma stem cells will be isolated from the tumoral mass excised during glioblastoma surgery in 35 patients; hematopoietic stem cells will be obtained from 10 consenting patients at the time of surgery by aspiration of 30-40ml of bone marrow from the iliac crests, as per standard clinical practice. Since the biopsy will be performed under general anesthesia, the patient should not experience discomfort.

There are no expected benefits for the individual patient, but the study results might provide important advances for the treatment of future patients.

Imaging and Biological Markers for Prediction and Identification of Glioblastoma Pseudoprogression: a Prospective Study.

To establish and characterize in vivo murine models of pseudoprogression by orthotopic transplantation of patient-derived GSCs in nonobese diabetic scid gamma (NSG) mice previously repopulated with individual patients' hematopoietic stem and progenitor cells to reproduce a humanized environment and to correlate in vivo imaging findings and plasma markers with pathology

predictive models (evaluation of specificity and sensitivity) using imaging advanced biomarkers, PET and MRI, biological serum markers, and cancer cell derived makers to differentiate tumor pseudoprogression or real progression in patients affected by GBM who underwent therapeutical protocol as per treating physicians' indications (Stupp or hypofractionated RT)

Glioblastoma stem cells (GSCs) will be isolated from the tumors of the patients enrolled, characterized at the molecular and functional level before and after in vitro treatment with radiations and TMZ, to identify candidate cellular phenotypes and molecular pathways possibly associated with pseudoprogression

Mediolanum Cardio Research

Istituto Clinico Humanitas

Research Administrator Manager

Symptoms and General Pathology

Blood and Lymph Conditions

Immune System Diseases

Nervous System Diseases

Substance Related Disorders

Syndrome

Lymphoma

Lymphoma, B-Cell

Cytokine Release Syndrome

Neurotoxicity Syndromes

Poisoning

Chemically-Induced Disorders

Lymphoma, Non-Hodgkin

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

B-cell Lymphoma

Single arm All patient will undergo an MRI with contrast injection, a blood withdrawal and a neurological consultation with neuropsychological tests

Magnetic Resonance Imaging with contrast injection

Blood withdrawal : serum, plasma, cytokine assay

Neuropsychological tests

The treatment of large-cell B-cell lymphomas refractory to more than 2 lines of therapy has recently been revolutionized by the use of immunotherapies consisting of autologous genetically modified cells or CAR-T CELLS (chimeric antigen receptor-T cells), which very significantly increase progression-free survival and overall survival. Nevertheless, this therapy is frequently associated with cytokine release syndrome and in approximately 20% to 60% of patients with neurological complications that can sometimes be dramatic and are associated with a significant mortality rate.

The mechanisms behind this neurotoxicity are unclear.

Despite the frequent occurrence of neurological toxicity characterized in particular by headache, tremor, and encephalopathy that is most often transient, brain imaging by CT or, preferably, MRI are most often normal. The rare abnormalities that have been identified suggest the presence of cytotoxic edema associated with the existence of transient modifications of the blood-brain barrier.

To date, the management of neurotoxicity associated with CAR-T CELLS remains empirical. It combines early management of cytokine release syndrome (by administration of anti-IL6) and treatment with corticosteroids, the objective of which would be to control neurotoxicity more specifically. A better understanding of the pathophysiological mechanisms associated with this neurotoxicity appears essential today in order to be able to propose adapted prevention and treatment methods.

Main objectives are to compare tissue permeability by quantitative MRI measurement of Ktrans to the theoretical peak of neurotoxicity between patients with CAR-T Cell-induced neurotoxicity and those without neurotoxicity and to Study, by MRI, the evolution of tissue microcirculatory parameters (from D-3 to D7) between groups of patients with or without the occurrence of neurotoxicity associated with CAR-T CELL treatment.

For this purpose, 25 subjects will be included (the investigators hypothesize 40% with treatment-induced neurological impairment).

The treatment of large-cell B-cell lymphomas refractory to more than 2 lines of therapy has recently been revolutionized by the use of immunotherapies consisting of autologous genetically modified cells or CAR-T CELLS (chimeric antigen receptor-T cells), which very significantly increase progression-free survival and overall survival. Nevertheless, this therapy is frequently associated with cytokine release syndrome and in approximately 20% to 60% of patients with neurological complications that can sometimes be dramatic and are associated with a significant mortality rate.

The mechanisms behind this neurotoxicity are unclear but may include :

* A "systemic" toxicity associated with the cytokine release syndrome. This toxicity would thus be favoured by the associated inflammatory response syndrome manifested in particular by hyperthermia, changes in blood pressure, and an increase in CRP, ferritin and the number of white blood cells.
* A breakdown of the blood-brain barrier, as evidenced by increased protein levels, cellularity and cytokine levels in the cerebrospinal fluid. Among other things, this rupture could be promoted by the synthesis of proinflammatory cytokines (IL6, TNF-alpha, IFN-gamma) that would promote endothelial activation.
* Direct toxicity to neurons and/or microglial cells.

Despite the frequent occurrence of neurological toxicity characterized in particular by headache, tremor, and encephalopathy that is most often transient, brain imaging by CT or, preferably, MRI are most often normal. The rare abnormalities that have been identified suggest the presence of cytotoxic edema associated with the existence of transient modifications of the blood-brain barrier.

To date, the management of neurotoxicity associated with CAR-T CELLS remains empirical. It combines early management of cytokine release syndrome (by administration of anti-IL6) and treatment with corticosteroids, the objective of which would be to control neurotoxicity more specifically. A better understanding of the pathophysiological mechanisms associated with this neurotoxicity appears essential today in order to be able to propose adapted prevention and treatment methods.

Objectives:

Main:

\* To Compare tissue permeability by quantitative MRI measurement of Ktrans to the theoretical peak of neurotoxicity between patients with CAR-T Cell-induced neurotoxicity and those without neurotoxicity.

Secondary:

* To Study, by MRI, the evolution of tissue microcirculatory parameters (from D-3 to D7) between groups of patients with or without the occurrence of neurotoxicity associated with CAR-T CELL treatment.
* To Correlate the values of the MRI parameters with the usual clinical and biological parameters known to be associated with the occurrence of neurotoxicity (at D0 and theoretical peak).
* To Correlate the values of the MRI parameters with the values (at D0 and at NADIR) of a panel of cytokines of interest (V-PLEX Neuroinflammation Panel Human 1 Kit, Meso Scale Discovery®).

Magnetic Resonance Imaging in Immune Effector Cell-Associated Neurotoxicity Syndrome

Contribution of Magnetic Resonance Imaging in Immune Effector Cell-Associated Neurotoxicity Syndrome

Quantitative measurement of KTRANS (rate of contrast agent transfer from plasma to the extravascular extracellular space, reflecting capillary permeability).

(Time in second)

FLAIR hypersignals analysis by MRI (signal of a tissue superior to the signal of the surrounding tissues) (visual assessment)

Analysis of contrast on injected 3DT1 MRI

AUC (area under the curve shows blood volume) (SI x Time)

Kep: rate of return transfer of the contrast agent from the extravascular extracellular space to the plasma (Volume/Time/Volume)

Ve: volume fraction of the extravascular space (Percentage %)

Vp: volume fraction of the plasma space. (Percentage %)

Cerebral blood flow analysis (3DPCASL) (L/min)

Cerebral volumetric analysis (3DT1) (cm3)

Perfusion factors (perfusion fraction f) (Percentage %)

Perfusion factors (pseudo-diffusion D\* at the microvascular compartment) (x10\^-3 mm²/s)

Presence, absence of neurotoxicity and inflammation

Comparison of MRI data with biological markers (such as CRP, ferritin, white blood cell count, LDH, procalcitonin, fibrinogen) and cytokine profile of neuroinflammation by multiplex immunoassay kit. An ultrasensitive multiplex using electrochemiluminescence.

University Hospital, Montpellier

Respiratory Tract (Lung and Bronchial) Diseases

Pleural Effusion

Neoplasm Metastasis

Pleural Diseases

Respiratory Tract Diseases

Solid cancer patients that have to undergo pleural evacuation because of diagnosed malignant pleural effusion mediated discomfort.

Cleo Goyvaerts, PhD

Lore Decoster, MD PhD

At the Laboratory for Molecular and Cellular Therapy (LMCT) of the Vrije Universiteit Brussel, Belgium, we study resistance mechanisms that hamper effective immunotherapy for solid cancer patients. To perform clinically relevant research, we apply autologous human material for functional assessment. The latter requires viable tumor and immune cells.

Solid cancer patients with pleural metastasis often develop pleural effusion. Notably, upon pleural drainage, residual material is obtained that consists of histocompatible tumor and immune cells. Hence with this study, we want to obtain blood and pleural effusion fluid drawn from solid cancer patients with pleural metastases to:

1. Collect, enrich and store primary cells derived from residual pleural effusion fluid and blood at the LMCT (VUB, Belgium)
2. Evaluate characteristics of the cells (phenotype, function,...) and compare content of pleural effusate with blood and clinicopathologic features of the patients.

Malignant pleural effusion (MPE) is characterized by the presence of malignant cells in the pleural cavity and develops in about 15% of patients with malignant disease. Two-thirds of all cases have a pleural effusion as one or sole initial manifestation of malignant disease. Primary tumors that most frequently develop MPE as metastatic disease are lung, breast cancer, and lymphoma accounting for 75% of all cases. Discomforting symptoms of MPE can include chest pain, cough, wheezing, hemoptysis, general discomfort, uneasiness, or ill feeling (malaise), shortness of breath and weight loss. To relief these discomforting symptoms, pleural drainage (evacuation) is routinely performed.

A significant number of solid cancer patients are currently being treated with immunotherapeutic drugs in first or second line or in the framework of a clinical trial. Aside from tumor cell intrinsic mechanisms, we and others previously found that non-malignant tumor infiltrated cells can also install immunotherapy resistance. Hence it remains of utmost importance to study the functional interactions between tumor cells and their non-malignant (solid) micro-environment to increase our current understanding of molecular profiles that predict responsiveness to immunotherapy. By exploiting patient-derived material, we aspire to perform more clinically relevant fundamental and translation research. The primary objective is to collect and compare blood, tumor and MPE-derived cell fractions. The secondary objective is to correlate cellular profiles with clinico-pathologic data.

Collection of Pleural Effusion Fluid

Collection of Pleural Effusion Fluid to Design Autologous Onco-immunological Assays

Samples will be pseudonymized and processed via RedCAP

Viable tissue will be processed to single cell suspensions at the research laboratory. Phenotype and function (= description of measurement) will be assessed using flow cytometry and in vitro immune assays (= measurement tools). Specifically we will evaluate the concentration and function of immune cells (derived from blood or pleural effusate like monocytes, macrophages, neutrophils and lymphocytes) and their interaction with autologous tumor cells (only derived from pleural effusate).

We will correlate demographics and biometrical data such as pre-disease history, therapy type, progression free and overall survival and tumor histology with the % of monocytes, macrophages, neutrophils and lymphocytes per patient (obtained from the Primary Outcome Measure). For this purpose, we will use statistical analysis via R software.

Vrije Universiteit Brussel

Universitair Ziekenhuis Brussel

Death

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Carcinoma

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

3 times Blood withdrawal for each patient (25ml each)

For each patient, 3 blood withdrawals of 25 ml each will take place during treatment

Dirk De Ruysscher, MD, PhD

In this exploratory study, the investigators will investigate if markers (molecular and immunological) of ICD or anti-tumor immunity (exosomal or molecular) can be detected in the serum of patients after high-dose radiotherapy alone or concurrent cisplatin-doublet therapy and radiotherapy. For each patient: withdraw blood at three times during treatment for analysis.

The main aim of anticancer therapies is to exert cytotoxic effects on cancer cells. It recently emerged that some anticancer therapeutic modalities are capable of inducing a cell death subroutine called immunogenic cell death (ICD) that can mediate specific, sustained anticancer immunity. These observations have marked the beginning of intense research into immunoadjuvant or anticancer immunity inducing "side-effects" associated with anticancer therapies.

At present, in humans, no ICD-associated predictive biomarkers have been identified, which hampers the development of immunological strategies. No published data about human biomarkers for ICD is available.

In vitro, ICD has been found to be associated with the spatiotemporally defined emission of danger signals such as surface exposed calreticulin (CRT) or heat shock protein 90 (HSP90), secreted ATP and released TLR4 agonists like HMGB1 or HSP70. Moreover, recently it has emerged that ICD may also be associated with a "viral response-like chemokine signature (VCS)" capable of acting as both 'find me' signal (for granulocytic myeloid cells) and 'keep away' signal (for immature monocytic myeloid cells) - further details of this paradigm are under investigation.

Thus, the presence of these molecular determinants of ICD can be used to monitor the host immune status and as a predictive biomarker. Examples include: danger signals as surrogate positive biomarkers (HMGB1, HSP70 and autoantibodies against CRT/HSP90); viral-response like chemokine signature as direct positive biomarkers (IFN1A, IFN1B and CXCL10\>CCL2\>CXCL1).

The presence of determinants of ICD can be confirmed through the strategy of following biomarkers (in non-hematological cancers):

* Cancer cell-associated pro-tumorigenic cytokines/factors IL1A, IL10, IL6, TGF-B, VEGFA, VEFGC, IDO enzyme, CXCL12, IL8
* Immune cell-associated pro-tumorigenic cytokines/chemokines/factors IL10, IDO enzyme, TGF-B, IL4, IL5, IL13, TNF, M-CSF, GM-CSF, IL26, CXCl5, CCL7
* danger signals as surrogate positive biomarkers HMGB1, HSP70 and autoantibodies against CRT/HSP90
* Cancer cell-associated viral response-like chemokine signature IFN-a, IFN-b, CXCL9, CXCL10, CXCL1 and CCL2
* Immune cell-associated anti-tumorigenic cytokines or chemokines as positive biomarkers IL1B, IL12p70, IL15, IFNG, IL22, IL23, IL17A, IL2, CCL4, CCL5, CXCL13, CCL8, CCL19, CXCL11,CCL12, CCL17, CCL23, CCL22, CCL13, CCL24, CCL1, CCL26, CXCL2, CXCL16 Moreover, the investigators will also investigate serum-associated exosomes as possible biomarkers of an efficient antitumor response. Compared to certain soluble biomarkers (which are accessible and thus more susceptible to extracellular proteases), exosomal biomarkers can exhibit a longer half-life than their soluble equivalents, due to the "protection" provided by their encompassing lipid membrane. Therefore, the investigators are also interested in exploiting exosomes as a source of antitumor response information and as novel biomarkers of therapeutic success (those mentioned above and others under investigation).

Radiotherapy has been established through various robust lines of in vitro and in vivo evaluation to be capable of inducing ICD and anticancer immune responses. As an exploratory analysis, we will integrate lipidomics into the workflow. This has already been done in multiple disease settings and NSCLC has already proven to change lipid content in a quantifiable manner. The aim of this pilot study is to investigate the hypothesis that certain biomarkers of ICD that were identified in vitro or ex vivo are detectable in patient sera following radiotherapy and/or chemotherapy. Radiotherapy alone or concurrent cisplatin-doublet and radiotherapy will be investigated. The investigator will conduct this pilot study to gather initial data to build upon in future clinical trials, as there is no in vivo data available on this topic. Results will be published and used for future grant applications.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Imaging and Biological Markers for Prediction and Identification of Glioblastoma Pseudoprogression: a Prospective Study.	NCT06113705	Glioblastoma	18F-GE-180 PET Advanced MRI Collection of h... Blood withdrawa... Collection of C...	18 Years -	Istituto Clinico Humanitas
Magnetic Resonance Imaging in Immune Effector Cell-Associated Neurotoxicity Syndrome	NCT05510596	Lymphoma, B-Cel... Neurotoxicity	Magnetic Resona... Blood withdrawa... Neuropsychologi...	18 Years -	University Hospital, Montpellier
Magnetic Resonance Imaging in Immune Effector Cell-Associated Neurotoxicity Syndrome	NCT05510596	Lymphoma, B-Cel... Neurotoxicity	Magnetic Resona... Blood withdrawa... Neuropsychologi...	18 Years -	University Hospital, Montpellier
Collection of Pleural Effusion Fluid	NCT05539183	Solid Tumor Pleural Effusio... Metastasis	Blood withdrawa...	18 Years -	Universitair Ziekenhuis Brussel
Detection of Circulating Biomarkers of Immunogenic Cell Death	NCT02921854	Non Small Cell ...	Blood withdrawa...	18 Years -	Maastricht Radiation Oncology

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