Abstract CT002: BNT211: A Phase I trial to evaluate safety and efficacy of CLDN6 CAR-T cells and CARVac-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumors
Authors: Haanen John BAG , Mackensen Andreas , Koenecke Christian , Alsdorf Winfried , Wagner-Drouet Eva , Heudobler Daniel , Borchmann Peter , Bokemeyer Carsten , Klobuch Sebastian , Desuki Alexander , Lüke Florian , Wiegert Erol , Schulz Catrine , Rengstl Benjamin , Preussner Liane , Türeci Özlem , Sahin Ugur 
Published: June 2022

Abstract
Background: BNT211 comprises two drug products, a chimeric antigen receptor (CAR)-T cell product candidate that targets the tumor specific antigen claudin 6 (CLDN6) and a CAR-T cell-Amplifying RNA Vaccine (CARVac). In mice, CARVac mediates expansion of adoptively transferred CAR-T cells, improving their persistence and functionality. BNT211 aims to establish CAR-T cell therapy for CLDN6-positive solid tumors.
Methods: This first-in-human, open label, multi-center trial involves a bifurcated 3+3 design with CLDN6 CAR-T cell dose escalations for both monotherapy (Part 1) and combination with CARVac (Part 2) following lymphodepletion. In Part 2, CARVac is applied q2/3w up to 100 days post CAR-T cell transfer, including a one-step intra-patient dose escalation followed by q6w maintenance dosing. Patients with CLDN6-positive relapsed or refractory solid tumors without further standard treatment options and ECOG 0-1 are eligible for recruitment.
Results: As of 19th Jan 2022, 16 patients have been treated, with CAR-T cell transfer performed at dose levels (DLs) 1 and 2 for parts 1 and 2. In total, 37 ≥G3 AEs related to the drug product (mainly cytopenia, or transaminase and lipase elevations without clinical correlates) and 2 DLTs (G4 cytopenia at DL2, part 1 and G4 hemophagocytic lymphohistiocytosis at DL2, part 2) were reported (all resolved). Pronounced cytopenia occurred in patients with testicular cancer who had recently received high-dose chemotherapy and autologous stem cell transplantation. For these patients a lymphodepletion-free/reduced cohort was recently opened. Analysis of CAR-T cell frequency in peripheral blood revealed robust engraftment in all patients, with peak engraftment around day 17. Manageable cytokine release syndrome (G1-2) without any signs of neurotoxicity was observed in 8 patients. Administration of CARVac resulted in transient flu-like symptoms resolving within 24 h. Preliminary efficacy data of 12 evaluable patients 6 weeks after infusion showed 5 patients with PRs (with 39-49% shrinkage of target lesions), 6 with SD and 1 patient with PD (ORR 42%; DCR 92%), with responses seen in testicular and ovarian cancer patients. At 12 weeks, 5 of the 6 patients with PRs showed deepening of responses (50-73% shrinkage). In addition, one testicular cancer patient was treated with a 50% lymphodepletion regime and showed PR after 6 weeks.
Conclusions: CLDN6 CAR-T cells ± CARVac show an acceptable safety profile at doses tested and encouraging signs of clinical activity. Data from the completed dose escalation phase will be presented. Acknowledgements: BNT211-01 is funded by BioNTech Cell & Gene Therapies GmbH.
Trial registration: Clinicaltrials.gov: NCT04503278.
Ethics approval: Ethics & Institutional Review Board approvals were obtained from the respective participating countries prior to initiation of the trial.
Citation Format: John BAG Haanen, Andreas Mackensen, Christian Koenecke, Winfried Alsdorf, Eva Wagner-Drouet, Daniel Heudobler, Peter Borchmann, Carsten Bokemeyer, Sebastian Klobuch, Alexander Desuki, Florian Lüke, Erol Wiegert, Catrine Schulz, Benjamin Rengstl, Liane Preussner, Özlem Türeci, Ugur Sahin. BNT211: A Phase I trial to evaluate safety and efficacy of CLDN6 CAR-T cells and CARVac-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT002.