Roger Stupp

Bio: Roger Stupp is an academic researcher from Northwestern University. The author has contributed to research in topics: Temozolomide & Glioma. The author has an hindex of 93, co-authored 430 publications receiving 63025 citations. Previous affiliations of Roger Stupp include Merck & Co. & University of St. Gallen.

Biom-39. p-erk association with overall survival in recurrent gbm patients treated with intracerebral administration of pd-1 and ctla-4 blocking antibodies

Abstract: Anti-PD-1 immunotherapy induces clinical responses in a subset of glioblastoma (GBM) patients. We previously reported that ERK1/2 phosphorylation (p-ERK) in pre-treatment tumor samples is predictive of overall survival (OS) following adjuvant anti-PD-1 therapy in two independent cohorts of recurrent GBM patients. Following the Remark criteria for biomarker validation, we investigated p-ERK as a predictive of OS in 24 evaluable tumor samples of recurrent GBM patients from a clinical trial. These patients underwent intracerebral administration of immune checkpoint inhibitors as part of a phase I clinical trial where intracerebral administration of ipilimumab (10 mg) or ipilimumab (5 mg) and nivolumab (10 mg) followed by postsurgical intravenous nivolumab (10 mg) was evaluated (NCT03233152; Duerinck J, et al. JITC, 2021). We quantified cell density of p-ERK+ cells in tumor regions. For exploratory purposes, patients were divided in 3 groups (n=8 per group) bases on p-ERK cell density. We observed an incremental OS with high p-ERK GBM patients exhibiting a median OS of 81.6 weeks (95% CI 33.86-NA), intermediate p-ERK median OS of 43.1 weeks (95% CI 33.14-NA), and low p-ERK group with a median OS of 19.3 weeks (95% CI 16.14-NA). A Cox proportional hazards model adjusted for age and IDH mutant status showed a trend for p-ERK association with favorable OS (HR= 0.77, 95% CI 0.6-=1.01, P=0.056). While the number of patients analyzed is relatively small, this study suggests the potential predictive power of p-ERK in an independent prospective GBM cohort treated with an alternative and unique administration approach of immune checkpoint blockade.

Ddel-13. ultrasound-enhanced delivery of liposomal doxorubicin across the blood brain barrier induces an ifn-gphenotype in microglia, macrophages, and t cells and improves response to pd-1 blockade in gliomas

Abstract: Given the limited drug penetration across the blood-brain barrier (BBB), the therapeutic potential of new and existing therapies has not been fully exploited for the benefit of glioblastoma (GBM) patients. Here we employed a novel drug delivery technology based on low-intensity pulsed ultrasound combined with intravenous microbubbles (LIPU/MB) that temporarily opens the BBB to deliver liposomal doxorubicin (DOX) and anti-PD-1 therapy (aPD-1) in mouse glioma models and 3 recurrent GBM patients. Immunological variables were evaluated in tumor and immune cells as well as efficacy in glioma-bearing mice treated with DOX delivered by LIPU. These included measurement of HLA ABC and HLA DR protein expression by tumor cells, microglia, and macrophages and IFN-g production by glioma-associated microglia and macrophages in mouse and human tumors. We also assessed efficacy of LIPU/MB enhanced combination therapy in glioma-bearing mice. Upregulation of HLA ABC and HLA DR was observed in GBM cell lines at low concentrations of DOX. Tumor cells from GBM patients treated with DOX, aPD-1 and LIPU/MB showed increased expression of HLA ABC and HLA DR compared to paired pretreatment samples. In both mice and humans, LIPU/MB liposomal DOX increased absolute brain drug concentrations and elicited a specific IFN-g phenotype and MHC I expression in glioma-associated microglia and macrophages in mice and humans. Furthermore, LIPU/MB-mediated BBB opening increased brain concentrations of aPD-1 in mice and in peritumoral regions of GBM patients. Combined treatment with liposomal DOX and aPD-1 delivered with LIPU/MB resulted in long-term survival of glioma-bearing mice that relied on the activity of CD8+ T cells for its efficacy. Overall, this translational study demonstrates the utility of LIPU/MB to stimulate intracranial immune responses in the context of treatment with DOX and aPD-1 for gliomas.

Advances in Blood-Brain Barrier Disruption to Facilitate Drug Delivery for Infiltrative Gliomas

Abstract: The blood-brain barrier (BBB) is a network of various interacting cell types (astrocytes, pericytes, microglia and endothelium), and features that are unique to the cerebral endothelium (tight junctions and transport proteins). The BBB limits the brain penetration of most circulating drugs, posing an impediment for treatment of infiltrative gliomas. Low-intensity pulsed ultrasound with microbubbles opens the BBB, facilitating the delivery of circulating drugs to the brain. Here we summarize valuable insights gained from preclinical experiments and early clinical trials evaluating this approach. We also highlight important questions related to this approach that warrant investigation in future clinical trials.

Gliome - was ich wissen muss in zehn Fragen Gliomas - What I Have to Know in ten Questions

Abstract: Zusammenfassung: Gliome sind die haufi gsten hirneigenen Tumoren und konnen sich mit einer Reihe von unspezifi schen neurologischen und Allgemeinsymptomen manifestieren. Der Goldstandard in der Diagnostik ist die zerebrale Magnetresonanztomografi e, welche durch eine histologische Diagnosesicherung erganzt werden muss. Zur symptomatischen Therapie kommen bei neurologischen Ausfallen und/oder Hirndrucksymptomatik Steroide, insbesondere Dexamethason und bei epileptischen Anfallen Antiepileptika zum Einsatz. Die Steroide sollten ausgeschlichen werden, sobald es klinisch vertretbar ist. Bei den Antiepileptika sind nicht-enzyminduzierende Medikamente zu bevorzugen. Bei Gliomen besteht ein hohes thrombembolisches Risiko. Nach einer Thrombose ist eine therapeutische Antikoagulation indiziert. Als tumorspezifi sche Therapie kommen die chirurgische Therapie, die Strahlentherapie und die systemische Therapie zum Einsatz. Bezuglich der Prognose und Therapieauswahl spielen molekulare Marker eine immer wichtigere Rolle in der onkologischen Praxis. Schlusselworter: Glioblastom – Oligodendrogliom – Antiepileptika – Thrombose – Steroide

Procédé de prédiction et de diagnostic d'une tumeur cérébrale

Abstract: L'invention concerne un procede permettant de predire ou de diagnostiquer le resultat d'une chimioradiotherapie concomitante mise en œuvre sur un sujet atteint d'une tumeur cerebrale. L'invention concerne de plus des compositions et a des methodes destinees a traiter ou a prevenir une resistance tumorale chez un sujet atteint d'une tumeur cerebrale, et une trousse servant a predire ou a diagnostiquer une resistance tumorale chez un sujet traite par une chimioradiotherapie concomitante.

Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

Abstract: methods Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. results A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients.

CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011.

Abstract: The Central Brain Tumor Registry of the United States (CBTRUS), in collaboration with the Centers for Disease Control (CDC) and National Cancer Institute (NCI), is the largest population-based registry focused exclusively on primary brain and other central nervous system (CNS) tumors in the United States (US) and represents the entire US population. This report contains the most up-to-date population-based data on primary brain tumors (malignant and non-malignant) and supersedes all previous CBTRUS reports in terms of completeness and accuracy. All rates (incidence and mortality) are age-adjusted using the 2000 US standard population and presented per 100,000 population. The average annual age-adjusted incidence rate (AAAIR) of all malignant and non-malignant brain and other CNS tumors was 23.79 (Malignant AAAIR=7.08, non-Malignant AAAIR=16.71). This rate was higher in females compared to males (26.31 versus 21.09), Blacks compared to Whites (23.88 versus 23.83), and non-Hispanics compared to Hispanics (24.23 versus 21.48). The most commonly occurring malignant brain and other CNS tumor was glioblastoma (14.5% of all tumors), and the most common non-malignant tumor was meningioma (38.3% of all tumors). Glioblastoma was more common in males, and meningioma was more common in females. In children and adolescents (age 0-19 years), the incidence rate of all primary brain and other CNS tumors was 6.14. An estimated 83,830 new cases of malignant and non-malignant brain and other CNS tumors are expected to be diagnosed in the US in 2020 (24,970 malignant and 58,860 non-malignant). There were 81,246 deaths attributed to malignant brain and other CNS tumors between 2013 and 2017. This represents an average annual mortality rate of 4.42. The 5-year relative survival rate following diagnosis of a malignant brain and other CNS tumor was 23.5% and for a non-malignant brain and other CNS tumor was 82.4%.

Comprehensive genomic characterization defines human glioblastoma genes and core pathways

Abstract: Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas - the most common type of primary adult brain cancer - and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol- 3- OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.

Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial

Abstract: BACKGROUND: In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. METHODS: Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353. FINDINGS: Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. INTERPRETATION: Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. FUNDING: EORTC, NCIC, Nelia and Amadeo Barletta Foundation, Schering-Plough.

MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma

Abstract: background Epigenetic silencing of the MGMT (O 6 -methylguanine–DNA methyltransferase) DNArepair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. methods We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. results The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. conclusions Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.