Ctim-04. Modulation of the Intratumoral Immune Microenvironment by Local Therapy With Natural Killer Cells Engineered With a Her2-targeted Chimeric Antigen Receptor in Combination With Systemic Anti-pd-1 Checkpoint Inhibition in Patients With Recurrent Glioblastoma
Year: 2024
Type: conference-abstract
Abstract: Glioblastoma (GB) is characterized by a marked immunosuppressive tumor microenvironment. In the multicenter CAR2BRAIN phase I first-in-human clinical trial, we investigated the modulation of the tumor microenvironment by repetitive local injection of clonal chimeric antigen receptor (CAR)-NK cells (NK-92/5.28.z) targeting HER2 alone and in combination with systemic anti-PD-1 checkpoint inhibitor therapy in patients with recurrent HER2-positive GB. 6 patients were treated with repetitive doses of CAR-NK cells as monotherapy and 12 patients received a combination therapy with the anti-PD-1 checkpoint inhibitor ezabenlimab. In three of those, we were able to implement a biopsy-treat-resect-treat strategy. After initial biopsy, combination treatment was initiated before planned tumor resection, enabling analysis of the transformation of the tumor immune microenvironment by highplex multispectral fluorescent analyses and cytokine quantification. None of the patients developed a cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Profound alterations of the immune cell distribution in the cerebrospinal fluid (CSF) and in the tumor were observed. In CSF sampled from the resection cavity, combination immunotherapy induced a local immune response with elevated pro-inflammatory cytokines and cell counts. In post-treatment tissue samples, we observed an increase of CD4+ and CD8+ T cells, and a decrease of regulatory CD4+FoxP3+ T cells. The three patients treated following the biopsy-treat-resect-treat strategy achieved a median progression-free survival (PFS) of 24 weeks, compared to 10 weeks for patients with upfront resection. Local immunotherapy with HER2-targeted CAR-NK cells is feasible and safe both as monotherapy and in combination with the systemic checkpoint inhibitor ezabenlimab and induces local immune reactions in CSF and tumor tissue. Given the signal for possible clinical benefit provided by the increase in PFS in the patients of the biopsy-treat-resect-treat cohort, further trials are warranted.
Source: Neuro-Oncology
Authors: Michael Burger, Elisabeth Ehrend, Florian Straßheimer, Pinar Cakmak, Harald Krenzlin, Philipp Elleringmann, Pia Zeiner, Stefanie Herkt, Isabel Poschke, Jadranka Macas, Katharina Weber, Jonathan Schupp, Jennifer Lun, Corinna Opitz, Bastian Roller, Patricia Manns, Svenja Klinsing, Stella Breuer, Stephanie Hehlgans, Seo-Youn Lee, Iris Mildenberger, Gleb Ludmirski, Julian Hermann, Elvira Müller, Marc Schmitz, Marcus Mehlitz, Christian Senft, Patrick Harter, Michael Rieger, Franz Rödel, Marcus Czabanka, Miriam Ratliff, Michael Platten, Christel Herold-Mende, Florian Ringel, Eva Herrmann, Elke Hattingen, Yvonne Reiss, Lukas Bunse, Halvard Bonig, Karl Plate, Marie-Therese Forster, Torsten Tonn, Winfried Wels, Joachim Steinbach
Institutions: Goethe University Frankfurt, German Cancer Research Center, University Hospital Frankfurt, Deutsches Konsortium für Translationale Krebsforschung, German Red Cross, Frankfurt Cancer Institute, University Medical Center of the Johannes Gutenberg University Mainz, National Center for Tumor Diseases, Heidelberg University, Medizinische Fakultät Mannheim, German Cancer Consortium (DKTK) Dresden, Technische Universität Dresden, Krankenhaus der Barmherzigen Brüder Trier, University Medical Centre Mannheim, University Hospital Heidelberg, Georg Speyer Haus
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4404237659