958 BNT211: a phase I/II trial to evaluate safety and efficacy of CLDN6 CAR-T cells and vaccine-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumors

Abstract

BackgroundBNT211 is a chimeric antigen receptor (CAR)-T cell product candidate that targets the tumor specific antigen Claudin-6 (CLDN6). Preclinical studies demonstrated that combining these engineered cells with a CAR-T cell Amplifying RNA Vaccine (CARVac) leads to in vivo expansion of adoptively transferred CAR-T cells, resulting in their improved persistence and functionality.MethodsThis first-in-human, open label, multi-center trial involves a bifurcated 3+3 design with separate CLDN6 CAR-T cell dose escalations (single flat-dose) for monotherapy (part 1) and the combination with CARVac (part 2) based on 3 dose levels (DL). In part 2, CARVac is applied every 3 weeks starting at day 4 post transplantation including a one-step intra-patient dose escalation. Patients with CLDN6-positive relapsed or refractory solid tumors without further standard treatment options and ECOG 0 or 1 are eligible for recruitment.ResultsAs of July 23rd 2021, 8 patients have been treated. DL1 of part 1 has been completed, while dosing of part 1 DL2 and part 2 DL1 is ongoing. One patient with cancer of unknown primary was treated with a dose below DL1 in combination with CARVac; the underlying diseases of the other 7 treated patients were testicular, ovarian and endometrial cancer as well as soft-tissue sarcoma. No acute or dose-limiting toxicities and no serious adverse events related to the drug product have been reported. Manageable cytokine release syndrome (CRS, grade 1-2, the latter managed with Tocilizumab) without any signs of neurotoxicity have been observed in both patients of part 1 DL2. Only transient and moderate elevations of IL-6 and CRP serum levels occurred in remaining patients. Notably, administration of CARVac resulted in transient flu-like symptoms resolving within 24h. Analysis of CAR-T cell frequency in peripheral blood revealed robust engraftment followed by decline after day 17. Further expansion was noted in two patients with liver metastases accompanied by elevated levels of ALT, AST and AP, while total bilirubin was not affected. First tumor assessment 6 weeks after transplantation available for 5/8 patients revealed 4 SD (3 transitioned into PD after an additional 6-18 weeks) and 1 PD. Strikingly, three patients showed initial tumor shrinkage according to RECIST1.1 (reduction of target sum: -18%, -21% and -27%).ConclusionsCLDN6 CAR-T cells +/- CARVac show a favorable safety profile at doses tested and encouraging signs of efficacy. Updated data from open cohorts and especially for combination with CARVac will be presented.AcknowledgementsBNT211-01 is funded by BioNTech Cell & Gene Therapies GmbH.Trial RegistrationClinicaltrialsgov: NCT04503278ReferencesN/A Ethics ApprovalEthics & Institutional Review Board approvals were obtained from the respective participating countries prior to initiation of the trial.ConsentN/A

Clinical advances and ongoing trials of mRNA vaccines for cancer treatment

“…A few trials have reported durable objective responses in patients with cancer after mRNA-based vaccine treatment, without unmanageable toxic effects. 10 , 14 , 15 , 16 , 19 mRNA vaccines are promising therapeutic candidates for future cancer treatments, especially in combination with additional immunotherapies. 14 , 19 , 20 However, no phase 3 studies are ongoing, and, at the time of writing, the US Food and Drug Administration (FDA) has not yet approved a therapeutic mRNA-based cancer vaccine.…”

“…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) …”

Nanoformulations targeting immune cells for cancer therapy: mRNA therapeutics

“… mRNA-5671 Phase-I Active, not recruiting (2019) NCT03948763 (G12D + G12V + G13D + G12C) advanced/metastatic cancers Splenic cDCs, pDCs, and macrophages Lipoplex CLDN6 Solid Tumor i.v. BNT211 Phase-I/II Recruiting NCT04503278 (2020) ([ 199 ]) Tumor-T cells, Tumor cells Cationic polymer/lipid formulation CD3 × CLDN6 bispecific antibodies Solid Tumor i.v. BNT142 Phase-I/II Recruiting NCT05262530 (2022) T cells LNP Optimized IL-2 Solid Tumor i.v.…”

Paving the Way to Solid Tumors: Challenges and Strategies for Adoptively Transferred Transgenic T Cells in the Tumor Microenvironment

“…Secondly, developmental antigens re-expressed in the tumor tissue display promising candidates for sufficient tumor specificity and, therefore, a reduced risk for off-tumor toxicity. The oncofetal protein Claudin 6 (CLDN6), virtually absent in normal body tissues, is aberrantly—but frequently—expressed in various cancer entities and therefore targeted by CAR-approaches [ 53 , 54 ]. Furthermore, so-called cancer-testis antigens (CTAs), only found in gametogenic tissue in the adult body otherwise, are reactivated during tumorigenesis.…”