Cancer
|

Phase I clinical trial of intracranial injection of CAR-engineered NK cells in patients with recurrent HER2-positive glioblastoma

Institution: Georg-Speyer-Haus, Institut für Tumorbiologie und experimentelle Therapie, Frankfurt am Main
Applicant: Prof. Dr. Winfried Wels
Funding line:
Translational Research
Image: Graphic

Co-applicants:

Prof. Dr. med. Torsten Tonn: DRK-Blutspendedienst
PD Dr. med. Michael Burger, Prof. Dr. med. Joachim Steinbach, Prof. Dr. med. Christian Senft: Zentrum der Neurologie und Neurochirurgie, Universitätsklinikum Frankfurt
Prof. Dr. med. Karl Plate: Edinger Institut, Universitätsklinikum Frankfurt
 

Project partner:

Universitätsklinikum Frankfurt
DRK-Blutspendedienst Frankfurt und Dresden


Project:

Expression of chimeric antigen receptors (CARs) in cytotoxic lymphocytes constitutes a promising strategy for adoptive cancer immunotherapy with effector cells of defined specificity. CARs are transmembrane proteins consisting of an extracellular tumor-specific single-chain antibody fragment (scFv) connected to one or more intracellular signaling domains, which trigger effector cell activation upon target antigen recognition. Besides T-lymphocytes, natural killer (NK) cells are increasingly being recognized as a valuable effector cell population for such approaches. Based on the clinically usable human NK cell line NK-92, the continuously expanding cell clone NK-92/5.28.z was generated that harbors a CAR specific for the tumor-associated antigen HER2 (ErbB2), which is expressed at elevated levels by a high proportion of glioblastomas and many other solid tumors.

GMP-compliant processes for expansion of clinical doses of NK-92/5.28.z cells were developed, and the investigator-initiated phase I clinical study CAR2BRAIN (NCT03383978, clinicaltrials.gov) was launched, initially carried out as a single-center trial at the Center for Neurology and Neurosurgery at the University Hospital Frankfurt in patients with recurrent or refractory HER2-positive glioblastoma. To establish feasibility and safety of this approach, in the recently completed dose escalation part of the trial, patients were treated by direct injection of a single dose of NK-92/5.28.z cells into the wall of the resection cavity during relapse surgery.

Image

In the second part of the study now funded by Else Kröner-Fresenius Foundation, patients of the expanson cohort receive, in addition to the first intraoperative injection of NK-92/5.28.z cells, repetitive injections of the cells into the resection cavity through an implanted catheter and reservoir. Several other participating study centers in Germany will contribute to this part of the protocol as a multicenter trial. Based on very promising data from preclinical glioblastoma models, the protocol was amended to include an additional cohort of patients treated with a combination of NK-92/5.28.z cells and an anti-PD-1 immune checkpoint inhibitor (CAR2BRAIN-CHECK).

Further information:

https://georg-speyer-haus.de/en/staff/wels-research/
https://www.uct-frankfurt.de/fuer-aerzte/klinische-studien/studienregister.html
https://clinicaltrials.gov/show/NCT03383978