CLDN6-specific CAR-T cells plus amplifying RNA vaccine in relapsed or refractory solid tumors: the phase 1 BNT211-01 trial

The oncofetal antigen Claudin 6 (CLDN6) is highly and specifically expressed in many solid tumors, and could be a promising treatment target. We report dose escalation results from the ongoing phase 1/2 BNT211-01 trial evaluating the safety and feasibility of chimeric antigen receptor (CAR) T cells...

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Veröffentlicht in:Nature medicine Jg. 29; H. 11; S. 2844 - 2853
Hauptverfasser: Mackensen, Andreas, Haanen, John B.A.G., Koenecke, Christian, Alsdorf, Winfried, Wagner-Drouet, Eva, Borchmann, Peter, Heudobler, Daniel, Ferstl, Barbara, Klobuch, Sebastian, Bokemeyer, Carsten, Desuki, Alexander, Lüke, Florian, Kutsch, Nadine, Müller, Fabian, Smit, Eveline, Hillemanns, Peter, Karagiannis, Panagiotis, Wiegert, Erol, He, Ying, Ho, Thang, Kang-Fortner, Qing, Schlitter, Anna Melissa, Schulz-Eying, Catrine, Finlayson, Andrew, Flemmig, Carina, Kühlcke, Klaus, Preußner, Liane, Rengstl, Benjamin, Türeci, Özlem, Şahin, Uğur
Format: Journal Article
Sprache:Englisch
Veröffentlicht: New York Nature Publishing Group US 01.11.2023
Nature Publishing Group
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Amplification
Antigens
Biomedical and Life Sciences
Biomedicine
Cancer Research
Chimeric antigen receptors
Clinical trials
Complications
Disease control
Infectious Diseases
Lymphocytes
Lymphocytes T
Manufacturing industry
Metabolic Diseases
Molecular Medicine
mRNA vaccines
Neurosciences
Neurotoxicity
Patients
Receptors
Response rates
Ribonucleic acid
RNA
Safety
Solid tumors
Tumors
Vaccines
ISSN:1078-8956, 1546-170X, 1546-170X
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Zusammenfassung:The oncofetal antigen Claudin 6 (CLDN6) is highly and specifically expressed in many solid tumors, and could be a promising treatment target. We report dose escalation results from the ongoing phase 1/2 BNT211-01 trial evaluating the safety and feasibility of chimeric antigen receptor (CAR) T cells targeting the CLDN6 with or without a CAR-T cell-amplifying RNA vaccine (CARVac) at two dose levels (DLs) in relapsed/refractory CLDN6-positive solid tumors. The primary endpoints were safety and tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D). Secondary endpoints included objective response rate (ORR) and disease control rate. We observed manageable toxicity, with 10 out of 22 patients (46%) experiencing cytokine release syndrome including one grade 3 event and 1 out of 22 (5%) with grade 1 immune effector cell-associated neurotoxicity syndrome. Dose-limiting toxicities occurred in two patients at the higher DL, resolving without sequelae. CAR-T cell engraftment was robust, and the addition of CARVac was well tolerated. The unconfirmed ORR in 21 evaluable patients was 33% (7 of 21), including one complete response. The disease control rate was 67% (14 of 21), with stable disease in seven patients. Patients with germ cell tumors treated at the higher DL exhibited the highest response rate (ORR 57% (4 of 7)). The maximum tolerated dose and RP2D were not established as the trial has been amended to utilize an automated manufacturing process. A repeat of the dose escalation is ongoing and will identify a RP2D for pivotal trials. ClinicalTrials.gov Identifier: NCT04503278 . In the ongoing phase 1/2 BNT211-01 trial, CLDN6-specific chimeric antigen receptor (CAR)-T cells given with or without CARVac, a CAR-T cell-amplifying RNA vaccine, were well-tolerated and exhibited encouraging clinical activity in patients with relapsed or refractory CLDN6-positive solid tumors, with the highest response rate in patients with germ cell tumors.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:1078-8956
1546-170X
1546-170X
DOI:10.1038/s41591-023-02612-0