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

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.

Clinical advances and ongoing trials of mRNA vaccines for cancer treatment

“…Indeed, patients receiving these combinations show encouraging clinical treatment responses across cancer diagnoses. 14 , 17 , 19 , 20 There is a need for new treatment combinations that increase response rates and progression-free survival without inducing severe side-effects, and an mRNA cancer vaccine with low toxicity is an obvious combination partner. Several trials are already combining mRNA vaccines with checkpoint inhibitors ( Table 1 , Table 2 , Table 3 ).…”

“…PFS and OS not improved 13 NCT01915524 1 MAGE-C1, MAGE-C2, NY-ESO-1, survivin, 5T4, and MUC-1 NSCLC (stage IV) 26 Local irradiation with or without pemetrexed, with or without EGFR-TKI Detectable antigen-specific immunity in 84% of patients One patient had PR in combination with chemotherapy treatment, and 46% had SD 14 LPX-formulation NCT02410733 1 NY-ESO-1, tyrosinase, MAGE-A3, TPTE Melanoma 25 (monotherapy) 17 (combination) With or without standard PD-1 therapy Immune responses against a minimum of one TAA in over 75% of patients mRNA vaccine with anti-PD-1 therapy: six patients had PR, and two had SD. mRNA vaccine monotherapy: three patients had PR, and seven had SD 15 NCT04503278 1/2 CLDN6 (CARVac) Solid tumours (CLDN6 CAR-T cells with CARVac) 7 CLDN6 CAR-T cells Engraftment of CAR-T cells in all patients Four patients had PR, and one patient had SD at 6-week evaluation 16 , 17 LNP-formulation NCT03480152 1/2 Neoantigen-specific mRNA Gastrointestinal cancer 4 None Mutation-specific CD4+ and CD8+ T-cell responses against predicted neoepitopes in three of four patients No objective clinical responses 18 NCT03313778 1 PCV encoding several neoantigens Solid tumours (resected) 13 (monotherapy) 19 (combination) …”

Efficacy, Safety, and Challenges of CAR T-Cells in the Treatment of Solid Tumors

“…Preclinical models showed that a CLDN6-encoding mRNA vaccine (CARVac) in combination with the CAR T-cell therapy favors CAR T-cell expansion and higher persistence in the blood. This, in turn, increase tumor cell killing [ 166 ].…”

Passive, active and endogenous organ-targeted lipid and polymer nanoparticles for delivery of genetic drugs

“…Combining the phospholipid DOPE and the permanently cationic lipid 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA) in a lipoplex enables mRNA delivery to antigen-presenting cells in the spleen, with potential applications in cancer immunotherapy 197 – 200 . Reducing the ratio of DOTMA to DOPE in the formulation, which leads to a negative net charge, allows functional mRNA delivery to the spleen without active targeting ligands 197 .…”

“…When loaded with mRNA encoding four tumour-associated antigens, the spleen-specific delivery of this nanoparticle resulted in objective responses in patients with melanoma, demonstrating the potential of mRNA as a modality for personalized cancer vaccines 198 . In another trial, an mRNA vaccine was used to boost the activity of chimeric antigen receptor T (CAR-T) cells targeting claudin 6 in solid tumours, in which CAR-T cells typically lack efficacy, leading to partial responses in patients with testicular or ovarian cancer 199 , 200 . The promising human trials data generated for these genetic vaccines suggest that organ-targeted delivery to lymphoid tissues by LNPs can unlock previously unattainable immunotherapy strategies in the clinic (Table 1 ).…”