CLDN6 CAR-T cell therapy of relapsed/refractory solid tumors ± a CLDN6-encoding mRNA vaccine: Dose escalation data from the BNT211-01 phase 1 trial using an automated product.

Andreas Mackensen Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany info_outline Andreas Mackensen, John B. A. G. Haanen, Christian Koenecke, Winfried Alsdorf, Eva Maria Wagner-Drouet, Daniel Heudobler, Peter Borchmann, Carsten Bokemeyer, Sebastian Klobuch, Nadine Kutsch, Fabian Müller, Alexander Desuki, Florian Lüke, Erol Wiegert, Carina Flemmig, Catrine Schulz-Eying, Benjamin Rengstl, Liane Preußner, Özlem Türeci, Uğur Şahin

Authors Andreas Mackensen Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany info_outline Andreas Mackensen, John B. A. G. Haanen, Christian Koenecke, Winfried Alsdorf, Eva Maria Wagner-Drouet, Daniel Heudobler, Peter Borchmann, Carsten Bokemeyer, Sebastian Klobuch, Nadine Kutsch, Fabian Müller, Alexander Desuki, Florian Lüke, Erol Wiegert, Carina Flemmig, Catrine Schulz-Eying, Benjamin Rengstl, Liane Preußner, Özlem Türeci, Uğur Şahin Organizations Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany, Netherlands Cancer Institute, Amsterdam, Netherlands, Hannover Medical School, Clinic for Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover, Germany, Department of Hematology and Oncology University Hospital Hamburg Eppendorf, Hamburg, Germany, University Medical Center Mainz, Mainz, Germany, University Hospital Regensburg, Regensburg, Germany, University Hospital of Cologne, Cologne, Germany, Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Netherlands Cancer Institute · Division of Medical Oncology, Amsterdam, Netherlands, Klinik I für Innere Medizin, Uniklinik Köln and Deutsche CLL Studiengruppe (DCLLSG), Köln, Germany, University Hospital of Erlangen, Erlangen, Germany, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz, Germany, University Hospital of Regensburg, Regensburg, Germany, Bexon Clinical Consulting LLC, Upper Montclair, NJ, Biontech, Mainz, Germany, BioNTech Cell & Gene Therapies, Mainz, Germany, BioNTech SE, Mainz, Germany, BioNTech, Mainz, Germany, BioNTech Corporation, Mainz, Germany Abstract Disclosures Research Funding Pharmaceutical/Biotech Company BioNTech SE Background: We are developing a chimeric antigen receptor (CAR)-T cell therapy targeting claudin 6 (CLDN6), an oncofetal antigen that is undetectable in healthy somatic tissue and highly expressed in various solid cancers. Autologous CLDN6 CAR-T cells are being tested alone and in combination with CLDN6-encoding CAR-T cell Amplifying RNA Vaccine (CARVac), a nanoparticulate RNA vaccine designed to stimulate and expand CLDN6 CAR-T cells. Methods: The ongoing first-in-human trial BNT211-01 evaluates the safety and feasibility of CLDN6 CAR-T cell transfer ± CARVac in lymphodepleted patients with relapsed/refractory solid tumors. Patients are pre-screened for CLDN6 expression with a cut-off of 50% positivity of intermediate or strong intensity by immunohistochemistry staining. Key endpoints are safety, tolerability, and anti-tumor activity. Pharmacokinetics of adoptively transferred CAR-T cells in peripheral blood is monitored by quantitative PCR. Dose escalation proceeds according to a classical 3+3 design, testing CLDN6 CAR-T cells at each dose level as both as monotherapy and in combination with CARVac. We previously reported results from 22 patients from 4 dose escalation cohorts with a manual CAR-T production process ± CARVac (ESMO-IO LBA38) which followed the same methodology. We observed durable responses along with a manageable safety profile, in line with commercial CAR-T products used to treat B-cell malignancies. No on-target/off-tumor toxicity and only a single case of (grade 1) neurotoxicity was observed. Given the encouraging efficacy, we have implemented an automated process to scale-up manufacturing. Accordingly, we are repeating the dose escalation with an automated CAR-T cell product, and with a modified CARVac regimen. As of 1 st February 2023, 7 patients with epithelial ovarian carcinoma (EOC), 4 with testicular germ cell tumors (GCT), and a further 5 patients with tumors of various indications have been infused with CAR-T cells up to DL2. We intend to submit efficacy, safety and CAR T-cell pharmacokinetics data from 5 cohorts treated with 1x10 6 , 1x10 7 or 1x10 8 CLDN6 CAR-T cells ± CARVac with a data cut-off of March 14 th , 2023 from ≥17 treated patients as a late-breaking abstract. Clinical trial information: NCT04503278.

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