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 RECURRE

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.

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Publication Details

Journal
Neuro-Oncology
Published
2024-11-01
DOI
https://doi.org/10.1093/neuonc/noae165.0338
Primary Topic
CAR-T cell therapy research
Type
article
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article

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 RECURRE

Elisabeth Ehrend, Marcus Mehlitz, Patrick N. Harter, Iris Mildenberger et al.
Neuro-Oncology
CAR-T cell therapy research
article

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 RECURRE

Elisabeth Ehrend, Marcus Mehlitz, Patrick N. Harter, Iris Mildenberger, G Ludmirski, Lukas Bunse, Michael C. Burger, Stephanie Hehlgans, Christel C. Herold‐Mende, Patricia J. Manns, F Straßheimer, Michael A. Rieger, Stefanie Herkt, Pia S. Zeiner, Isabel Poschke, Jonathan Schupp, Corinna Opitz, Franz Rödel, Jadranka Macas, Torsten Tonn, Stella Breuer, Svenja Klinsing, Christian Senft, Seo-Youn Lee, Winfried S. Wels, Jennifer H. Lun, Elvira Müller, Michael Platten, Eva Herrmann, Pinar Cakmak, Marcus Czabanka, Elke Hattingen, Joachim P. Steinbach, Marc Schmitz, Florian Ringel, Halvard Bönig, Katharina Johanna Weber, Miriam Ratliff, Harald Krenzlin, Yvonne Reiss, Marie-Thérèse Forster, P Elleringmann, Karl H. Plate, Bastian Roller, Julian Hermann
article en

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.

Neuro-OncologyVol. 26(Supplement_8)
Goethe University Frankfurt (DE), German Cancer Research Center (DE), Johannes Gutenberg University Mainz (DE), Heidelberg University (DE), German Red Cross (DE), University Hospital Heidelberg (DE), Krankenhaus der Barmherzigen Brüder Trier (DE), Institute for Transfusion Medicine (US), University Medical Center of the Johannes Gutenberg University Mainz (DE), National Center for Tumor Diseases (DE), Institute of Immunology (HR), University Hospital Frankfurt (DE), Carl Gustav Carus-Institut (DE), Georg Speyer Haus (DE), University Medical Centre Mannheim (DE), Frankfurt Cancer Institute (DE), University Hospital Carl Gustav Carus (DE), Deutsches Konsortium für Translationale Krebsforschung (DE), Technische Universität Dresden (DE)
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Openalex Percentile: Top 64%
CAR-T cell therapy research
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