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. 2023 Nov 2;25(11):2058-2071.
doi: 10.1093/neuonc/noad087.

Intracranial injection of natural killer cells engineered with a HER2-targeted chimeric antigen receptor in patients with recurrent glioblastoma

Michael C Burger  1   2 , Marie-Therese Forster  3 , Annette Romanski  4 , Florian Straßheimer  1   2 , Jadranka Macas  2   5   6   7 , Pia S Zeiner  1   2 , Eike Steidl  8 , Stefanie Herkt  4 , Katharina J Weber  2   5   6   7   9 , Jonathan Schupp  2   5   6   7 , Jennifer H Lun  2   5   6   7 , Maja I Strecker  1   2 , Karolin Wlotzka  1   2 , Pinar Cakmak  2   5   6   7 , Corinna Opitz  10 , Rosemol George  6   11 , Iris C Mildenberger  1 , Paulina Nowakowska  4 , Congcong Zhang  12 , Jasmin Röder  2   12 , Elvira Müller  1   2 , Kristina Ihrig  9 , Karl-Josef Langen  13   14 , Michael A Rieger  2   6   7   15 , Eva Herrmann  16 , Halvard Bonig  4 , Patrick N Harter  2   5   6   7 , Yvonne Reiss  2   5   6   7 , Elke Hattingen  8 , Franz Rödel  2   6   11 , Karl H Plate  2   5   6 , Torsten Tonn  10   17 , Christian Senft  3 , Joachim P Steinbach  1   2 , Winfried S Wels  2   6   12
Affiliations

Intracranial injection of natural killer cells engineered with a HER2-targeted chimeric antigen receptor in patients with recurrent glioblastoma

Michael C Burger et al. Neuro Oncol. .

Abstract

Background: Glioblastoma (GB) is incurable at present without established treatment options for recurrent disease. In this phase I first-in-human clinical trial we investigated safety and feasibility of adoptive transfer of clonal chimeric antigen receptor (CAR)-NK cells (NK-92/5.28.z) targeting HER2, which is expressed at elevated levels by a subset of glioblastomas.

Methods: Nine patients with recurrent HER2-positive GB were treated with single doses of 1 × 107, 3 × 107, or 1 × 108 irradiated CAR-NK cells injected into the margins of the surgical cavity during relapse surgery. Imaging at baseline and follow-up, peripheral blood lymphocyte phenotyping and analyses of the immune architecture by multiplex immunohistochemistry and spatial digital profiling were performed.

Results: There were no dose-limiting toxicities, and none of the patients developed a cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Five patients showed stable disease after relapse surgery and CAR-NK injection that lasted 7 to 37 weeks. Four patients had progressive disease. Pseudoprogression was found at injection sites in 2 patients, suggestive of a treatment-induced immune response. For all patients, median progression-free survival was 7 weeks, and median overall survival was 31 weeks. Furthermore, the level of CD8+ T-cell infiltration in recurrent tumor tissue prior to CAR-NK cell injection positively correlated with time to progression.

Conclusions: Intracranial injection of HER2-targeted CAR-NK cells is feasible and safe in patients with recurrent GB. 1 × 108 NK-92/5.28.z cells was determined as the maximum feasible dose for a subsequent expansion cohort with repetitive local injections of CAR-NK cells.

Keywords: CAR; HER2; NK cells; adoptive immunotherapy; glioblastoma; human clinical trial; in; phase I first.

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Conflict of interest statement

CZ, TT, and WSW are named as inventors on patents and patent applications related to the study therapeutic owned by their respective academic institutions. MCB received honoraria for lectures or advisory board participation from Bristol Myers Squibb and Gilead Sciences. CS received honoraria for lectures, advisory board participation, expert testimony, or travel support from Stryker, Bayer, Brainlab, and Novocure. JPS received grants from Merck and UCB as well as honoraria for lectures, travel, or advisory board participation from Abbvie, Bristol-Myers Squibb, Medac, Roche, Novocure, and UCB. HB acknowledges speakers’ and advisory board honoraria from Boehringer-Ingelheim, Bristol Myers Squibb, Novartis, Sandoz-Hexal, and Medac as well as royalties and licensing fees from Medac, all unrelated to the work presented herein. No potential conflicts of interest were disclosed by the other authors.

Figures

Figure 1.
Figure 1.
CONSORT Flow Diagram.
Figure 2.
Figure 2.
Treatment response. (A) Progression-free (PFS) and overall survival (OS) of patients treated with NK-92/5.28.z cells. Dose levels, time points of initiation of consecutive treatments, and subsequent additional relapse surgeries are indicated. Best response was stable disease (SD) for patients CB001, CB003, CB009, CB010, CB011, and progressive disease (PD) for patients CB004, CB005, CB007. (B) Magnetic resonance imaging (MRI) showing spot-like contrast enhancements in the resection margin in patient CB011 detected 12 and 18 weeks after local NK-92/5.28.z injections as a possible correlate of an induced immune reaction. (C) 18F-FET positron emission tomography indicating pseudoprogression in patient CB011.
Figure 3.
Figure 3.
Spatial analysis of the tumor microenvironment and correlation with progression-free and overall survival following chimeric antigen receptor (CAR)-NK therapy. (A) Composite images showing Opal 6-color multiplex immunofluorescence stainings for CD3 (green), CD8 (yellow), Iba-1 (red), CD163 (cyan) and von Willebrand Factor (vWF, magenta) to identify T lymphocytes, myeloid, and endothelial cells. DAPI was used to detect nuclei (blue). Individual images of primary (treatment-naïve, upper panel) and recurrent (post radiation and chemotherapy with temozolomide, lower panel) glioma tissues of patient CB001 are shown. Scale bars: 100 µm. (B) Simple linear regression analysis revealing an increase in the proportion of CD8+ T-cells in recurrent tumor tissues prior to CAR-NK therapy as a significant predictor for progression-free (P = .0002, R2 = 0.8796) and overall survival (P = .0093, R2 = 0.6432). (C) Kaplan–Meier survival analysis post CAR-NK therapy based on CD8+ T-cell frequency in recurrent tumor tissues. Statistical significance was assessed using the Log-rank test.
Figure 4.
Figure 4.
Spatial analysis of immune cell subpopulations in the course of disease progression. Multiplex immunofluorescence images of regions of interests selected within whole slide scans derived from primary, recurrent and post chimeric antigen receptor (CAR)-NK therapy tumor tissues of patients CB007 (A) and CB011 (B) are displayed. Two different staining panels to detect CD3, CD8, CD163, Iba-1, vWF, DAPI (mixed panel; scale bars: 100 µm), and CD8, CD4, PD-1, FoxP3, Ki-67, DAPI (lymphoid panel; scale bars: 50 µm) were employed. Staining with the lymphoid panel is shown for recurrent tumor tissue as an example.
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Comment in

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