10 Klinische Forschung/Studien

10

Klinische Forschung/Studien

Wir entwickeln und führen jährlich mehr als 50 klinische Studien durch. Unsere Patient:innen können so vom neuesten Stand der Wissenschaft und von neu verfügbaren Therapieansätzen profitieren.

In der MOH Studienzentrale arbeiten >15 Studienkoordinator:innen und Study Nurses. Sie kümmern sich um den gesamten Ablauf von Öffnung, Durchführung und Dokumentation von klinischen Studien der Phase I–IV. Im Jahr 2021 haben wir >170 Patient:innen in >50 klinische Studienprotokolle rekrutiert.

Wir sind eins von der Schweizerischen Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK) zertifiziertes Phase-I-Zentrum und können somit das ganze Spektrum an frühen Studien anbieten, von Dosisfindungsstudien bis zu Studien mit Medikamenten, welche zum ersten Mal am Menschen eingesetzt werden (first-in-human clinical trials).

Wir arbeiten eng mit (inter)nationalen Netzwerken zusammen. Dazu gehören die SAKK, die European Organisation for Research and Treament of Cancer (EORTC) und die European Thoracic Oncology Platform (ETOP).

Offene, diagnostische und interventionelle klinische Studienprotokolle (2021)

Phase

Phase I & I/II

Phase II

Phase III

Andere

Gesamt* Anzahl der Studien

8

16

22

7

53 Eingeschlossene Patient:innen

9

41

120

3

173

Clinical Trial Highlights

J CLIN INVEST. 2022 JUN 15;132(12):E158190

Antibodies from convalescent plasma promote SARS-CoV-2 clearance in individuals with and without endogenous antibody response

M Marconato, IA. Abela, A Hauser, M Schwarzmüller, R Katzensteiner, DL Braun, S Epp, A Audigé, J Weber, P Rusert, E Schindler, C Pasin, E West, J Böni, V Kufner, M Huber, M Zaheri, S Schmutz, BM Frey, RD Kouyos, HF Günthard, MG Manz, A Trkola

Abstract

Background: Neutralizing antibodies are considered a key correlate of protection by current SARS-CoV-2 vaccines. The manner in which human infections respond to therapeutic SARS-CoV-2 antibodies, including convalescent plasma therapy, remains to be fully elucidated. Methods: We conducted a proof-of-principle study of convalescent plasma therapy based on a phase I trial in 30 hospitalized COVID-19 patients with a median interval between onset of symptoms and first transfusion of 9 days (IQR, 7–11.8 days). Comprehensive longitudinal monitoring of the virological, serological, and disease status of recipients allowed deciphering of parameters on which plasma therapy efficacy depends. Results: In this trial, convalescent plasma therapy was safe as evidenced by the absence of transfusionrelated adverse events and low mortality (3.3%). Treatment with highly neutralizing plasma was significantly associated with faster virus clearance, as demonstrated by Kaplan-Meier analysis (P = 0.034) and confirmed in a parametric survival model including viral load and comorbidity (adjusted hazard ratio, 3.0; 95% CI, 1.1–8.1; P = 0.026). The onset of endogenous neutralization affected viral clearance, but even after adjustment for their pretransfusion endogenous neutralization status, recipients benefitted from plasma therapy with high neutralizing antibodies (hazard ratio, 3.5; 95% CI, 1.1–11; P = 0.034). Conclusion: Our data demonstrate a clear impact of exogenous antibody therapy on the rapid clearance of viremia before and after onset of the endogenous neutralizing response, and point beyond antibody-based interventions to critical laboratory parameters for improved evaluation of current and future SARS-CoV-2 therapies. Trial Registration: ClinicalTrials.gov NCT04869072. Funding: This study was funded via an Innovation Pool project by the University Hospital Zurich; the Swiss Red Cross Glückskette Corona Funding; Pandemiefonds of the UZH Foundation; and the Clinical Research Priority Program “Comprehensive Genomic Pathogen Detection” of the University of Zurich.

“This truly interdisciplinary study, including clinical infectiology, hematology, virology, and the blood donation center, demonstrates the unique value of academic clusters, able to raplidly respond to public health challenges for the benefit of patients.”

BLOOD. 2020 APR 30;135(18):1548-1559

Clonal hematopoiesis in donors and long-term survivors of related allogeneic hematopoietic stem cell transplantation

S Boettcher, CM Wilk, J Singer, F Beier, E Burcklen, C Beisel, MS Ventura Ferreira, E Gourri, C Gassner, BM Frey, U Schanz, RC Skoda, BL Ebert, H Brummendorf, N Beerenwinkel, MG Manz

Abstract

Clonal hematopoiesis (CH) is associated with age and an increased risk of myeloid malignancies, cardiovascular risk, and all-cause mortality. We tested for CH in a setting where hematopoietic stem cells (HSCs) of the same individual are exposed to different degrees of proliferative stress and environments, ie, in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their respective related donors (n = 42 donor-recipient pairs). With a median follow-up time since allo-HSCT of 16 years (range, 10-32 years), we found a total of 35 mutations in 23 out of 84 (27.4%) study participants. Ten out of 42 donors (23.8%) and 13 out of 42 recipients (31%) had CH. CH was associated with older donor and recipient age. We identified 5 cases of donor-engrafted CH, with 1 case progressing into myelodysplastic syndrome in both donor and recipient. Four out of 5 cases showed increased clone size in recipients compared with donors. We further characterized the hematopoietic system in individuals with CH as follows: (1) CH was consistently present in myeloid cells but varied in penetrance in B and T cells; (2) colony-forming units (CFUs) revealed clonal evolution or multiple independent clones in individuals with multiple CH mutations; and (3) telomere shortening determined in granulocytes suggested 20 years of added proliferative history of HSCs in recipients compared with their donors, with telomere length in CH vs non-CH CFUs showing varying patterns. This study provides insight into the long-term behavior of the same human HSCs and respective CH development under different proliferative conditions.

“This research work shows for the first time the behavior of the donor blood stem cell system in both the donor and recipient over 10–33 years beyond transplantation. It demonstrates accelerated ageing but also the remarkable stability and efficacy of blood formation from hematopoietic stem cells.”

Clinical Trial Highlights

ANN ONCOL. 2021 JAN;32(1):120-121

Local delivery of CAR T cells targeting fibroblast activation protein is safe in patients with pleural mesothelioma: first report of FAPME, a phase I clinical trial

S Hiltbrunner, C Britschgi, P Schuberth, L Bankel, T D L Nguyen-Kim, P Gulati, W Weder, I Opitz, O Lauk, C Caviezel, H Bachmann, A Tabor, P Schröder, A Knuth, C Münz, R Stahel, O Boyman, C Renner, U Petrausch, A Curioni-Fontecedro

Abstract

Malignant pleural mesothelioma (MPM) is a cancer derived from mesothelial cells growing in the thoracic cavity with few treatment options. Despite the use of multi-modality approaches, the median survival after diagnosis does not exceed two years. Adoptive cell transfer of genetically engineered chimeric antigen receptor (CAR) T cells has shown great success in hematological malignancies, but are still under investigation in solid tumors. Due to the confined spread of MPM, local delivery of CAR T cells might overcome a major challenge in CAR T cell treatment, namely successful homing to the tumor tissue. Here, we report the data of the first phase I clinical trial (NCT01722149) using fibroblast activation protein (FAP) targeting CAR T cells (CART-FAP) injected into the pleural cavity of MPM patients. FAP is highly expressed on all MPM subtypes including the patients reported in this trial, but not on healthy adult tissues. The aim of the study was to determine the toxicity and feasibility of this treatment. All patients included had histologically or cytologically confirmed metastatic MPM and were medically and/or functionally not inaccessible for surgical treatment, with all patients receiving three cycles of chemotherapy before CART-FAP administration. All patients had adequate bone marrow, hepatic and renal function, without corticosteroids treatment. Four patients were included in this trial; one patient did not receive CAR T cells due to low expansion rate after retroviral transduction. Patients were continuously monitored for the first 48 h after CART-FAP transfer. Safety assessments included incidence of treatment-related adverse events, according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 4.0. In two patients, a thromboembolic event occurred and resolved; these events were considered unrelated to study treatment but possibly to active cancer, chemotherapy or the presence of an indwelling catheter. Safety board evaluation felt the study could continue after review. We injected one million CART-FAP cells; this is the lowest recommended dose for second generation CAR T cells (CD28 signaling domain) and it has been selected as FAP has not been previously investigated as a target. Although this subtherapeutic dose, we detected systemic expansion of CART-FAP cells in the blood peaking in one out of three patients at 21 days after intrapleural infusion. This finding indicates that a local administration of CART-FAP can lead to systemic distribution. Furthermore, all CAR T cell products were proven to be highly specific in vitro and this translated to elevated concentrations of proinflammatory cytokines in patients’ sera, indicating an ongoing immune response.

“This study is one of the first academically generated CAR-T cells studies in patients with solid tumors. It demonstrates the safety of the approach and provides the ground for further clinical research in this highly promising area of immunotherapy.”

LUNG CANCER. 2020 AUG;146:217-223

Survival outcome of non-small cell lung cancer patients: Comparing results between the database of the Comprehensive Cancer Center Zurich and the Epidemiological Cancer Registry Zurich and Zug

R A Stahel, A Curioni-Fontecedro, S Rohrmann, U Dafni, U Sandner, I Opitz, N Andratschke, D Franzen, G Dimopoulou, K L Matthes, M Kohler, M Guckenberger, W Weder

Abstract

Background: Cancer cases among the population of the canton Zurich, are registered in the Cancer Registry of the cantons of Zurich and Zug (KKR). The Thoracic Oncology Center, founded in 2011 is one of 17 multidisciplinary centers within the Comprehensive Cancer Center Zurich (CCCZ). Methods: The aim of the current study is to quantify the mortality risk of patients with NSCLC and identify differences on survival and other factors between patients receiving their primary treatment at the CCCZ and those treated elsewhere and registered by KKR. The differential effect between CCCZ and KKR cohorts on survival: overall, by stage, sex and age, is explored. Stratified log-rank and Wilcoxon tests, Cox models and restricted mean survival times (RMST) are estimated. Propensity score matching (PSM) is also used to adjust for confounding factors. Results: Analysis included 848 NSCLC cases from the CCCZ and 1759 from the KKR, diagnosed between January 2011 and December 2015. At a median follow-up of 57 months, overall survival (OS) was significantly superior for patients treated at the CCCZ compared to KKR [Median OS: 36.0 months (95%CI: 31.0-45.0) and 12.0 months (95%CI: 11.0-13.0), respectively, stratified log-rank p < 0.001; adjusted HR = 1.31, (95% CI: 1.18-1.46), difference in RMST up to 72 months: 13.8 months (95%CI: 11.5-16.2), p < 0.001]. The effect of cohort was significant for stages III and IV (overall and also by sex and age). After PSM OS remained significantly superior for patients treated at the CCCZ compared to KKR. Conclusion: The survival probability for patients in the CCCZ cohort was superior to that of patients in the canton Zürich treated outside the center. This analysis provides further evidence of the importance of the volume of experience and the availability of a multidisciplinary organization and research environment, as delivered by a comprehensive cancer center, on the outcome of patients with NSCLC. Keywords Cancer center; Cancer registry; Multidisciplinary; Non-small cell lung cancer; Outcome; Sex and age; Stage.

“This retrospective analysis re-confirms what has been shown now in multiple analysis: treatment of patients in a comprehensive cancer center setting is associated with a survival advantage compared to other clinical settings. We take this as encouragement for our effort to provide best possible therapies for all our patients.”