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

被引：64

作者：

Burger, Michael C. ^{[1
,2
]}

Forster, Marie-Therese ^{[3
]}

Romanski, Annette ^{[4
,5
]}

Strassheimer, Florian ^{[1
,2
]}

Macas, Jadranka ^{[2
,6
,7
,8
]}

Zeiner, Pia S. ^{[1
,2
]}

Steidl, Eike ^{[9
]}

Herkt, Stefanie ^{[4
,5
]}

Weber, Katharina J. ^{[2
,6
,7
,8
,10
]}

Schupp, Jonathan ^{[2
,6
,7
,8
]}

Lun, Jennifer H. ^{[2
,6
,7
,8
]}

Strecker, Maja, I ^{[1
,2
]}

Wlotzka, Karolin ^{[1
,2
]}

Cakmak, Pinar ^{[2
,6
,7
,8
]}

Opitz, Corinna ^{[11
]}

George, Rosemol ^{[7
,12
]}

Mildenberger, Iris C. ^{[1
,19
]}

Nowakowska, Paulina ^{[4
,5
]}

Zhang, Congcong ^{[13
]}

Roeder, Jasmin ^{[2
,13
]}

Mueller, Elvira ^{[1
,2
]}

Ihrig, Kristina ^{[10
]}

Langen, Karl-Josef ^{[14
,15
]}

Rieger, Michael A. ^{[2
,7
,8
,16
]}

Herrmann, Eva ^{[9
,17
]}

Bonig, Halvard ^{[4
,5
]}

Harter, Patrick N. ^{[2
,6
,7
,8
,20
]}

Reiss, Yvonne ^{[2
,6
,7
,8
]}

Hattingen, Elke

Roedel, Franz ^{[2
,7
,12
]}

Plate, Karl H. ^{[2
,6
,7
]}

Tonn, Torsten ^{[11
,18
]}

Senft, Christian ^{[3
,21
]}

Steinbach, Joachim P. ^{[1
,2
]}

Wels, Winfried S. ^{[2
,7
,13
]}

机构：

[1] Goethe Univ Hosp, Dr Senckenberg Inst Neurooncol, Frankfurt, Germany

[2] Goethe Univ, FCI, Frankfurt, Germany

[3] Goethe Univ Hosp, Dept Neurosurg, Frankfurt, Germany

[4] Goethe Univ, Inst Transfus Med & Immunohematol, Frankfurt, Germany

[5] Red Cross Blood Donat Serv Baden Wurttemberg Hess, Frankfurt, Germany

[6] Goethe Univ Hosp, Inst Neurol, Edinger Inst, Frankfurt, Germany

[7] German Canc Consortium DKTK, Partner Site Frankfurt Mainz, Frankfurt, Germany

[8] German Canc Res Ctr, Heidelberg, Germany

[9] Goethe Univ Hosp, Inst Neuroradiol, Frankfurt, Germany

[10] Goethe Univ Hosp, UCT, Frankfurt, Germany

[11] Tech Univ Dresden, Inst Transfus Med, Med Fac Carl Gustav Carus, German Red Cross Blood Donat Serv North East, Dresden, Germany

[12] Goethe Univ Hosp, Dept Radiotherapy & Oncol, Frankfurt, Germany

[13] Georg Speyer Haus, Inst Tumor Biol & Expt Therapy, Frankfurt, Germany

[14] Res Ctr Julich, Inst Neurosci & Med, Julich, Germany

[15] Univ Hosp Aachen, Dept Nucl Med, Aachen, Germany

[16] Goethe Univ Hosp, Dept Med 2, Hematol Oncol, Frankfurt, Germany

[17] Goethe Univ, Inst Biostat & Math Modelling, Frankfurt, Germany

[18] German Canc Consortium DKTK, Partner Site Dresden, Dresden, Germany

[19] Heidelberg Univ, Dept Neurol, Med Fac Mannheim, Mannheim, Germany

[20] Ludwig Maximilians Univ Munchen, Ctr Neuropathol & Pr Res, Munich, Germany

[21] Jena Univ Hosp, Ctr Neurooncol, Dept Neurosurg, Jena, Germany

来源：

NEURO-ONCOLOGY | 2023年 / 25卷 / 11期

关键词：

adoptive immunotherapy; CAR-NK cells; glioblastoma; HER2; phase I first-in-human clinical trial; NK-92; CELLS; CLINICAL-TRIAL; CANCER-CELLS; IMMUNOTHERAPY; EXPRESSION; THERAPY; SAFETY;

D O I：

10.1093/neuonc/noad087

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 x 10(7), 3 x 10(7), or 1 x 10(8) 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 x 10(8) 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.

引用

页码：2058 / 2071

页数：14

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