Project

Back to overview

Defining novel targets for chimeric antigen receptor (CAR)-based immunotherapy against glioblastoma

English title Defining novel targets for chimeric antigen receptor (CAR)-based immunotherapy against glioblastoma
Applicant Roth Patrick
Number 170027
Funding scheme Project funding (Div. I-III)
Research institution Neurologische Klinik Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Experimental Cancer Research
Start/End 01.07.2017 - 31.12.2020
Approved amount 372'000.00
Show all

Keywords (4)

immunotherapy; chimeric-antigen receptor; Brain tumor; glioblastoma

Lay Summary (German)

Lead
Immuntherapeutische Behandlungsansätze haben in den letzten Jahren zu einer erheblichen Verbesserung der Prognose zahlreicher Tumorerkrankungen geführt. Beim Glioblastom, einem Tumor des Gehirns, sind die therapeutischen Fortschritte bisher jedoch noch vergleichsweise gering, was u.a. daran liegt, dass sich die immunologische Situation im zentralen Nervensystem von der in anderen Teilen des Körpers unterscheidet.
Lay summary

Ein neues immuntherapeutisches Konzept besteht darin, Immunzellen aus dem Blut zu isolieren, so zu modifzieren, dass eine spezifische Erkennung von Tumorzellen zu einer unmittelbaren Aktivierung führt und diese modifizierten Immunzellen dann zu infundieren. Im Rahmen des laufenden Projekts werden wir Immunzellen so verändern, dass 2 neue Zielstrukturen, die auf Gliomzellen vorhanden sind, als therapeutische Angriffspunkte genutzt werden. Wir werden diesen Ansatz in einem Gliommodell prüfen und versuchen, die Wirksamkeit der generierten Zellen mit Hilfe weiterer Behandlungsmethoden zu kombinieren, um einen möglichst optimalen Therapieeffekt zu erreichen. Langfristiges Ziel ist eine Übertragung des Konzepts in eine klinische Studie bei Menschen, die an einem Glioblastom leiden.

 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Im Rahmen des Projekts sollen die Voraussetzungen für eine spätere Anwendung am Menschen geschaffen werden. Da die Diagnose eines Glioblastoms mit einer sehr ungünstigen Prognose einhergeht, sind neue Behandlungsansätze dringend erforderlich, um den Betroffenen bessere Therapieoptionen anbieten zu können.

Direct link to Lay Summary Last update: 26.06.2017

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
132847 Growth and differentiation factor (GDF)-15, microRNA and the immunophenotype of glioblastoma 01.02.2011 Project funding (Div. I-III)
177080 MIG-ART - MRI gestützte adaptive Radio-Onkologie 01.06.2018 R'EQUIP

Abstract

Glioblastomas are the most common intrinsic brain tumors with a poor prognosis despite some therapeutic progress within the last years. They are characterized by diffuse infiltration of the surrounding healthy brain tissue and regarded as paradigmatic for suppressing anti-tumor immune responses. Glioma cells accumulate various genetic alterations that could enable their recognition as “altered self” by the immune system. However, tumor-derived factors which suppress immune functions are a substantial barrier to effective antitumor immunity in vivo. Despite these obstacles, immunotherapy has been considered a promising therapeutic approach against glioblastoma for decades. Because of the limited success of various strategies such as vaccination, other immunotherapeutics need to be explored in order to translate them into the clinic. Within the present proposal, we aim at characterizing the anti-glioma activity of T cells genetically engineered to express a chimeric antigen receptor (CAR). We will use 2 CAR constructs that recognize different targets on the cell surface of glioma cells. First, we will assess the anti-glioma activity of CAR T cells which express an NKG2D-CAR. NKG2D is a naturally occurring NK and T cell receptor. Upon binding of one of the several NKG2D ligands which are expressed on glioma cells, T cells equipped with the NKG2D-CAR are strongly activated which shall result in specific tumor cell killing. Based on preliminary data obtained with NKG2D-CAR T cells generated in our laboratory demonstrating that this concept is working in vitro, we aim at assessing the therapeutic benefit derived from CAR T cell therapy in appropriate syngeneic mouse glioma models. In order to exploit already available therapeutic strategies in combination with the CAR T cell concept, we will define whether radiotherapy or alkylating chemotherapy with temozolomide, which represent the standard treatment for glioblastoma, act synergistically with the adoptive transfer of NKG2D-CAR T cells. This hypothesis is supported by preliminary findings of our laboratory demonstrating that exposure to temozolomide or irradiation at sublethal doses leads to increased NKG2DL levels on glioma cells. Thus, we expect that radiochemotherapy may further boost the activity of NKG2D-CAR T cell because of increased target expression on glioma cells. Finally, we will combine CAR T cell transfer with the administration of immune checkpoint inhibitors which will increase the probability of obtaining sufficient anti-glioma CAR T cell responses in vivo. In a second part of this proposal, we will assess a novel target for CAR-based treatment against glioblastoma. We have already shown that CD317, a cell surface molecule with largely unknown function, is expressed by glioma cells in vitro and in vivo but not on healthy brain tissue. Accordingly, CD317 may represent a novel and promising target for CAR T cell-based treatment. As a preparation for this proposal, we have already generated a CAR construct specifically recognizing human CD317. Similar to the planned experiments with the NKG2D-CAR, we will assess the anti-glioma activity of CD317-specific CAR T cells against various glioma cell lines including glioma-initiating cells. This will be followed by appropriate in vivo experiments using intratumoral administration of CAR T cells as well as systemic injection of these cells. All in vivo experiments are accompanied by appropriate ex vivo analyses of explanted tumors regarding CAR T cell infiltration and the activation status of these cells.In summary, this research proposal aims at defining novel targets for CAR T cell-based treatment against glioblastoma. We can build up on the long-lasting experience of our laboratory in the field of glioma immunobiology and expect that the studies outlined in this proposal will help to develop novel therapeutic strategies which can subsequently be examined in a study with human patients and ultimately translate into clinical benefit.
-