Patrick Roth

University of Geneva | UNIGE · IT Division

BACKGROUND Chimeric antigen receptor (CAR) T-cell therapy, while effective against hematological malignancies, has faced significant hurdles in its application to solid tumors. Challenges in CAR T-cell therapy for glioblastoma include the immunosuppressive tumor microenvironment, the limited infiltration of CAR T-cells into the tumor, heterogeneous...

Effective treatment options for meningioma patients beyond surgical resection and radiotherapy are limited. This study presents preclinical and translational evidence supporting the efficacy of an adaptor CAR-T cell system targeting Somatostatin Receptor (SSTR) 2 in otherwise untreatable meningiomas. Tissue microarray analysis revealed that SSTR2 e...

The advent of cancer neuroscience has significantly advanced our understanding of brain tumor biology, yet the clinical implications remain largely unexplored. Glutamate, the most abundant excitatory neurotransmitter, presents a potential therapeutic target in brain tumors. Glioblastoma cells synthesize and secrete large amounts of glutamate, drivi...

BACKGROUND Somatostatin receptor (SSTR) 2 has been proposed as a target to deliver therapeutic agents to gliomas. The SSTR2 antagonist peptide octofluo was developed to redirect fluorescein-5-isothiocyanate (FITC)-specific adapter chimeric antigen receptor (AdCAR)-T cells towards SSTR2-expressing tumor cells. MATERIAL AND METHODS A tissue microarr...

BACKGROUND Within the treatment of the most common and aggressive brain tumors - gliomas - the last decades have been characterized by an enormously high rate of failed and cost-intensive drug trials. Repurposing established medications for the treatment of cancer has the advantage of faster availability as well as cost-effectiveness. Chloroquine (...

BACKGROUND Glioblastoma is the most common malignant brain tumor with a devastating outcome. Novel therapeutic strategies are currently explored including the use of chimeric antigen receptor (CAR) T cells. However, in glioblastoma an impaired tumor infiltration by CAR T cells, antigen heterogeneity and an immunosuppressive tumor microenvironment r...

L’e-assessment ou évaluation numérique consiste à faire passer un examen sur un dispositif numérique (Viberg et al., 2024), que ce soit à distance ou en salle. Elle peut s’appliquer aussi bien dans un contexte formatif que sommatif. Lors de la pandémie de COVID et les périodes de confinement, l’évaluation numérique s’est largement imposée comme le...

Proposition : L'e-assessment ou évaluation numérique consiste à faire passer un examen sur un dispositif numérique (Viberg et al., 2024), que ce soit à distance ou en salle. Elle peut s'appliquer aussi bien dans un contexte formatif que sommatif. Lors de la pandémie de COVID et les périodes de confinement, l'évaluation numérique s'est largement imp...

2058 Background: There has been little progress in the treatment of newly diagnosed glioblastoma in decades and standards of care for recurrent glioblastoma remain poorly defined. The multi-cyclin dependent kinase inhibitor Zotiraciclib (TG02) depletes short-lived survival proteins such as c-MYC and MCL-1 which are overexpressed in glioblastoma. Th...

Background Standard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT) and temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that c...

Background and Objectives Hydrocephalus is a common radiologic sign in patients with leptomeningeal metastasis (LM) from solid tumors which can be assessed using the Evans index (EI). Here, we explored the prognostic value of ventricular size in LM. Methods We identified patients with LM from solid tumors by chart review at 3 academic hospitals to...

Background Glioblastoma is the most common and most aggressive malignant primary brain tumor in adults. Glioblastoma cells synthesize and secrete large quantities of the excitatory neurotransmitter glutamate, driving epilepsy, neuronal death, tumor growth and invasion. Moreover, neuronal networks interconnect with glioblastoma cell networks through...

Prognostic factors and standards of care for astrocytoma, isocitrate dehydrogenase (IDH)-mutant, CNS WHO grade 4, remain poorly defined. Here we sought to explore disease characteristics, prognostic markers, and outcome in patients with this newly defined tumor type. We determined molecular biomarkers and assembled clinical and outcome data in pati...

PURPOSE To study disease characteristics, prognostic markers and outcome in patients with isocitrate dehydrogenase (IDH)-mutant astrocytoma by CNS WHO grade. EXPERIMENTAL DESIGN We determined molecular biomarkers and assembled clinical and outcome data in a cohort of 258 patients with IDH-mutant astrocytomas (114 CNS WHO grade 2, 73 CNS WHO grade...

INTRODUCTION The phase 2 REGOMA trial suggested a survival benefit of the multikinase inhibitor regorafenib for treating patients with glioblastoma at first recurrence. Hand-foot skin reactions (HFSR) following multikinase inhibitor therapy have been reported to predict prolonged overall survival (OS) in patients with solid tumors. The predictive v...

BACKGROUND Patients with progressive diffuse gliomas have limited treatment options. DLL3, a Notch ligand, is expressed on most diffuse gliomas. BI 764532, a humanized IgG-like T cell engager, binds selectively to DLL3-positive cells and promotes T cell-mediated cytotoxicity. Preclinical data showed activity of BI 764532 against intracranial tumors...

BACKGROUND Zotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor that is supposed to suppress tumor growth via CDK-9-dependent depletion of survival proteins such as c-MYC and MCL-1 which are frequently overexpressed in glioblastoma. METHODS EORTC 1608 (NCT03224104) (STEAM) had a three parallel group (A,B,C) phase Ib, open-l...

BACKGROUND Chimeric antigen receptor (CAR-)T cell therapy, a powerful immunotherapy against hematological malignancies, has so far limited efficiency in solid tumors. Also in glioblastoma, a major obstacle remains limited infiltration of CAR-T cells into the tumor. Vessel-targeting CAR-T cells have been shown to infiltrate solid tumors more efficie...

Adoptive transfer of engineered immune cells expressing chimeric antigen receptors (CAR) is an emerging cancer immunotherapy that is also being investigated for glioblastoma. Many separate studies focus on either CAR T or CAR NK cells, and CAR macrophages are in early stages of development. However, a systemic cross-comparison of engineered immune...

Glioblastoma synthesizes and secretes large quantities of the excitatory neurotransmitter glutamate, driving epilepsy, neuronal death, tumor growth and invasion. Several brain-penetrating drugs that have obtained clinical approval in other pathologic conditions can inhibit glutamate synthesis, secretion and signalling, respectively, including (i) t...

Treatment options for recurrent glioblastoma are limited and there is a need for novel effective therapies. Recently, we showed synergistic preclinical anti-tumor activity of the immunocytokine L19TNF in combination with lomustine in orthotopic immunocompetent glioma mouse models. L19TNF is an antibody-cytokine fusion protein, comprising the pro-in...

BACKGROUND The standard of care for patients with newly diagnosed glioblastoma includes maximum safe resection followed by radiotherapy (RT) with concomitant and maintenance temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). Among potential new therapeutic strategies, targeting the proteasome has been considered promising because of its implication in n...

BACKGROUND: Debio 0123 is an oral, brain-penetrant, highly selective WEE1 inhibitor. WEE1 inhibition leads to S phase and G2/M cell cycle checkpoint abrogation, permitting mitosis without DNA repair, leading to mitotic catastrophe and subsequent cell death. Preclinically, Debio 0123 has been shown to effectively penetrate the brain and demonstrated...

Background Incidence rates of glioblastoma in very old patients are rising. The standard of care for this cohort is only partially defined and survival remains poor. The aims of this study were to reveal current practice of tumor-specific therapy and supportive care, and to identify predictors for survival in this cohort. Methods Patients aged 80...

BACKGROUND Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined. METHODS European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry study s...

BACKGROUND Treatment options for recurrent glioblastoma are limited and there is a need for novel effective therapies. Cytokine-based therapies are promising cancer immunotherapies that potentially can convert an immunologically “cold” tumor microenvironment into a “hot” one and may trigger potent antitumor immunity. However, the systemic administr...

BACKGROUND The phase 2 REGOMA trial suggested a survival benefit of the multikinase inhibitor regorafenib for the treatment of patients with glioblastoma at first recurrence. Hand-foot skin reactions (HFSR) following multikinase inhibitor therapy have been reported as a predictor for prolonged survival in patients with solid tumors. Data on the pre...

BACKGROUND Hydrocephalus is a common radiological sign in patients with leptomeningeal metastasis (LM) from solid tumors and can be assessed using the Evans index (EI) with high interrater agreement. Here we explored the prognostic value of ventricular size at diagnosis and during the disease course of LM. METHODS We assembled a cohort of 113 adul...

BACKGROUND Chimeric antigen receptor (CAR) T cell therapy has emerged as a potent immunotherapy against hematological malignancies. In glioblastoma, however, limited infiltration of the tumor by CAR T cells, tumor heterogeneity, antigen escape and an immunosuppressive tumor microenvironment remain significant obstacles. Vessel-targeting CAR T cells...

BACKGROUND Effective treatment options for meningioma patients beyond surgical resection and radiotherapy are lacking. Somatostatin receptor (SSTR) 2 is expressed by most meningiomas. Here, we report pre-clinical and translational evidence for the activity of an SSTR2-targeted adaptor CAR T cell system in meningiomas. MATERIAL AND METHODS Tissue m...

The MakeITeasy platform is the backbone of the University of Geneva's "Digital Skills" institutional project. The objective of the system is to allow the actors, students, teachers, researchers, administrative and technical staff to develop and strengthen their digital skills. It is a matter of allowing individuals to evaluate themselves to self-re...

BACKGROUND Hydrocephalus is a common radiological sign in patients with leptomeningeal metastasis (LM) from solid tumors and can be assessed using the Evans index (EI) with high interrater agreement. Here we explored the prognostic value of ventricular size at diagnosis and during the disease course of LM. METHODS We assembled a cohort of 113 adul...

Meningiomas are the most common primary intracranial tumors. Although most symptomatic cases can be managed by surgery and/or radiotherapy, a relevant number of patients experience an unfavorable clinical course and additional treatment options are needed. As meningiomas are often perfused by dural branches of the external carotid artery, which is...

Background: Chimeric antigen receptor (CAR) T cell therapy has proven to be successful against hematological malignancies. However, exploiting CAR T cells to treat solid tumors is more challenging for various reasons including the lack of suitable target antigens. Here, we identify the transmembrane protein CD317 as a novel target antigen for CAR...

The MakeITeasy platform is the backbone of the University of Geneva's "Digital Skills" institutional project. The objective of the system is to allow the actors, students, teachers, researchers, administrative and technical staff to develop and strengthen their digital skills. It is a matter of allowing individuals to evaluate themselves to self-re...

2044 Background: Lisavanbulin (BAL101553, prodrug of BAL27862) destabilizes microtubules and promotes tumor cell death by modulating the spindle assembly checkpoint. BAL27862 is a lipophilic small molecule shown in rodents to penetrate the brain, with antitumor activity in orthotopic glioblastoma (GBM) models. In the Phase 1 part of this study ¹ (N...

2054 Background: Zotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor, including CDK-9, that inhibits tumor growth down-stream via depletion of survival proteins such as MCL-1 and MYC. MCL-1 and MYC are frequently overexpressed in glioblastoma. Methods: The EORTC 1608 (NCT03224104) (STEAM) phase 1b trial had a three parallel...

2016 Background: Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined. Methods: European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry s...

2033 Background: Hydrocephalus is a common radiological sign in patients with leptomeningeal metastasis (LM) from solid tumors and can be assessed using the Evans index (EI) with high interrater agreement. Normal ranges of EI values have been defined as 0.27 ± 0.05 for females and 0.28 ± 0.06 for males aged 65-69 for the diagnostic work-up of demen...

Glioblastoma is the most aggressive primary brain tumor with an unmet need for more effective therapies. Here, we investigated combination therapies based on L19TNF, an antibody-cytokine fusion protein based on tumor necrosis factor that selectively localizes to cancer neovasculature. Using immunocompetent orthotopic glioma mouse models, we identif...

Background: Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined. Methods: European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry stu...

Background: Established models for prognostic assessment in patients with brain metastasis do not stratify for prior surgery. Here we tested the prognostic accuracy of the Graded Prognostic Assessment (GPA) score model in patients operated for BM and explored further prognostic factors. Methods: We included 285 patients operated for brain metast...

The hepatocyte growth factor (HGF)/MET signaling pathway has been proposed to be involved in the resistance to radiotherapy of glioblastoma via proinvasive and DNA damage response pathways. Here we assessed the role of the MET pathway in the response to radiotherapy in vitro and in vivo in syngeneic mouse glioma models. We find that the murine glio...

Central nervous system (CNS) tumor patients commonly undergo multimodality treatment in the course of their disease. Adverse effects and complications from these interventions have not been systematically studied, but pose significant challenges in clinical practice and impact function and quality of life, especially in the management of long-term...

Purpose. Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862), a microtubule-destabilizing agent. The goal of this study (NCT02895360) was to characterize the safety, tolerability and antitumor activity of lisavanbulin administered as a 48-hour intravenous (IV) infusion at the recommended Phase 2 dose (RP2D) of 70 mg/m2. Results from the...

Despite multimodal treatment approaches including surgery, radiotherapy and chemotherapy, the median survival for patients with glioblastoma remains in the range of one year and thus poor. Type I interferons (IFN) are involved in immune responses to viral infection and exhibit anti-tumor activity in certain cancers. Here we explored the biological...

Background Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common adverse event of CD19-directed chimeric antigen receptor (CAR) T cell therapy. Other neurological adverse events, however, have not methodically been described and studied. Furthermore, safety data on CAR-T cell therapy in patients with central nervous system (CNS...

La plateforme MakeITeasy constitue l’épine dorsale du projet institutionnel « Digital Skills » de l’Université de Genève. L’objectif du dispositif est de permettre aux acteurs, étudiants, enseignants, chercheurs, personnel administratif et technique, de s’orienter pour s’approprier le développement et le renforcement de leurs compétences numériques...

RATIONALE Innovative treatment strategies are urgently needed to improve the prognosis of glioblastoma patients. Chimeric antigen receptor (CAR) T cell therapy has shown great success in hematological malignancies. However, it remains to be shown that CAR T cells are also active against solid tumors. αv integrins are overexpressed in gliomas and ha...

Glioblastoma is the most aggressive primary brain tumor and adults and poorly immunogenic. Treatment options for recurrent glioblastoma after standard of care chemoradiation are limited Several immunotherapeutic strategies including peptide vaccination and immune checkpoint inhibition have so far failed to improve survival and except from potential...

Currently, immunotherapy is one of the most promising research areas in oncology, but immunotherapeutic strategies do not have proven clinical activity against glioblastoma so far. The immunosuppressive microenvironment of gliomas limits an appropriate anti-tumor immune response and represents a major challenge in the context of immunotherapy. Ther...

Seizures are a frequent symptom in patients with glioblastoma and bear a relevant impact on quality of life. Likewise, anti-epileptic treatment may affect patients’ well-being due to side effects. Here, we assessed whether owing to relieve from edema and intracranial pressure, treatment with bevacizumab for recurrent glioblastoma might contribute t...

Purpose: The low mutational load of some cancers is considered one reason for the difficulties to develop effective tumor vaccines. To overcome this problem, we developed a strategy to design neopeptides through single amino acid mutation to enhance their immunogenicity. Experimental design: Exome- and RNA sequencing as well as in silico HLA-bin...

Background Glioblastoma is the most common brain tumor in adults and virtually incurable. Therefore, new therapeutic strategies are urgently needed. Immune checkpoint inhibition has not shown activity in various phase III trials and intra- as well as intertumoral expression of programmed death ligand 1 (PD-L1) varies in glioblastoma. Methods We ab...

Background Treatment options for recurrent glioblastoma are limited and with the possible exception of regorafenib, no agent has demonstrated superior activity to lomustine. Therefore, there is an urgent need for more effective treatment strategies for recurrent glioblastoma. Here, we investigated different treatment combinations based on the tumor...

Background CD317 is an interferon-inducible cell surface receptor expressed in several solid cancer types. HM1.24-ETA’ is a small immunotoxin with a CD317 single-chain variable fragment (svFv) antibody fused to a truncated version of Pseudomonas aeruginosa exotoxin A (ETA’) that is explored as a novel therapeutic approach in CD317-expressing tumors...

Background Glioblastoma remains to be one of the most lethal solid cancers. Despite multi-modal therapy including surgery as safely feasible, radiotherapy and chemotherapy with the alkylating agent temozolomide, the median survival of affected patients is still limited to approximately one year on a population level. Thus, novel therapies are urgen...

Background Current standard of care for glioblastoma patients has limited therapeutic efficacy and novel innovative treatment strategies are urgently needed. One such strategy is chimeric antigen receptor (CAR) T cell therapy that has shown great success in hematological malignancies. αv integrins are overexpressed in several neoplasms and have alr...

Purpose: Most chimeric antigen receptor (CAR)-T cell strategies against glioblastoma have demonstrated only modest therapeutic activity and are based on persistent gene modification strategies that have limited transgene capacity, long manufacturing processes and the risk for uncontrollable off-tumor toxicities. mRNA-based T cell modifications are...

The management of primary central nervous system (PCNSL) is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the limited number of controlled studies available. In 2021, given recent advances and publication of practice-changing randomised trials, the European Association of Neuro-Oncology (EANO) c...

Seizures in patients with brain metastases have an impact on morbidity and quality of life. The influence of tumor growth on the risk of seizures in these patients is not well defined. In this cohort study, we evaluated adult patients from the University Hospital of Zurich following resection of brain metastases from solid tumors, with or without p...

Seizures are a frequent symptom in patients with glioblastoma and bear a relevant impact on quality of life.1–3 Retrospective studies have indicated that temozolomide may improve seizure control in glioma patients.2,4 Bevacizumab, an approved treatment for recurrent glioblastoma,³ may also decrease seizure frequency, eg, by reducing edema, with pot...

Background: Venous thromboembolic events (VTE) are a major complication in cancer patients, and therefore, also in brain cancer patients, anticoagulants are considered appropriate in the treatment of VTE. Methods: Frequency, risk factors and treatment of VTE, as well as associated complications were assessed in a population-based cohort of gliob...

BACKGROUND Addition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in glioblastoma, but previous studies suggest that patients with tumors harboring an unmethylated MGMT promoter derive minimal benefit. The aim of this open-label, phase 3 CheckMate 498 study was to evaluate the efficacy of nivolumab (NIVO)+RT compared wit...

The transforming growth factor (TGF)-β signaling pathway has been recognized as a major factor in promoting the aggressive behavior of glioblastoma, isocitrate dehydrogenase-wildtype. However, there is little knowledge about the expression of TGF-β receptors in glioblastoma. Here, we studied the expression patterns of TGF-β receptor II (TGFβRII), t...

Background Validation of the 2016 RANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. Accordingly, this joint EORTC Brain Tumor Group and RANO effort sought to prospectively validate a revised MRI scorecard for response assessment in leptomeningeal metastasis. Methods Coded paired cerebrospinal MRI of 20 patients with lep...

Les référentiels de littératie numérique sont des outils de médiation. Ceux issus de la recherche ou d’instances éducatives précisent des dimensions (« pensée critique », « production de contenus numériques ») facilitant une médiation stratégique. Comment transformer ces référentiels pour faciliter une médiation pédagogique ? Deux éléments apparais...

Glioblastoma remains one of the deadliest cancers despite aggressive treatment, which is why novel therapeutic approaches are urgently needed. Chimeric antigen receptor (CAR) T cell therapy has demonstrated significant success in the field of hematological malignancies. However, treating glioblastoma with this type of therapy is more difficult for...

Glioblastoma remains to be one of the most lethal solid cancers and novel therapies are urgently needed. There is increasing interest in the role of the HGF/MET pathway in the response of glioblastoma to radiotherapy. c-MET-mediated radioresistance may be partially induced via proinvasive and DNA damageresponse pathways and HGF may be involved in t...

The profound local immunosuppressive microenvironment is one hallmark of glioblastoma, which results in resistance to most immunotherapeutic strategies that have been explored so far. Reverting this condition in order to reinvigorate anti-glioma immunity might be a promising therapeutic approach. Transforming growth factor (TGF)-β signaling is dere...

BACKGROUND Validation of the 2016 LANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. The objective of this joint EORTC Brain Tumor Group and RANO effort was to validate the feasibility of the revised MRI scorecard for assessing response in leptomeningeal metastasis. METHODS Coded paired cerebrospinal MRI of 20 patients w...

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 use...

Treatment options for recurrent glioblastoma are limited and there is a need for novel effective therapies. We previously demonstrated encouraging anti-tumor activity with the targeted delivery of tumor necrosis factor a (TNF) in preclinical orthotopic glioma models. TNF- a is a potent pro-inflammatory cytokine which may trigger strong anti-tumor i...

BACKGROUND Due to the limited success of existing therapies for gliomas, innovative therapeutic options are urgently needed. Chimeric antigen receptor (CAR) T cell therapy has been successful in patients with hematological malignancies. However, using