LBA38 BNT211-01: A phase I trial to evaluate safety and efficacy of CLDN6 CAR T cells and CLDN6-encoding mRNA vaccine-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumours

Abstract

BNT211 is a potential first-in-class therapeutic approach for claudin 6 (CLDN6)-positive solid tumors with two components: chimeric antigen receptor (CAR) T cells targeting the tumour-specific antigen CLDN6 and a CLDN6-encoding CAR T cell-Amplifying RNA Vaccine (CARVac) designed to expand adoptively transferred CAR T cells and improve their persistence. This is a first-in-human trial (NCT04503278) in patients (pts) with CLDN6-positive relapsed/refractory solid tumours, ECOG PS 0/1 and no further standard treatment options. Following lymphodepletion, the bifurcated 3+3 design comprises CLDN6 CAR T cell dose escalations for monotherapy and combined with CLDN6 CARVac, applied repeatedly after CAR T infusion with one intra-pt dose escalation (25→50 μg). Key primary endpoint is safety and tolerability. As of 15 Jun 2022, 22 pts had been treated, mainly with testicular (13) and ovarian (4) cancers. 7 pts were treated at dose level (DL) 1 (107 CAR T cells/pt; including 1 pt with <107 cells) and 13 pts at DL2 (108 CAR T cells/pt; including 1 pt with a 50% lymphodepletion regimen and 2 pts with no lymphodepletion). 2 pts had dose-limiting toxicities: 1/6 at DL2 monotherapy (pancytopenia), and 1/7 at DL2 + CARVac (hemophagocytic lymphohistiocytosis). Most treatment-emergent adverse events ≥G2 were related to lymphodepletion or asymptomatic transaminase/lipase elevations. Cytokine release syndrome (CRS) was ≤G2, except for 1 pt with no lymphodepletion who had G3 CRS (all resolved). 7/21 evaluable pts (per RECIST v1.1, 6 wks post-infusion) had PR, 8 had SD (6 with target lesion shrinkage) and 6 had PD (including 2 deaths before assessment); as 1 pt was infused with <107 cells they were non-evaluable. 5 pts with testicular cancer responded at 6 wks, with CAR T-cell persistence and further tumour shrinkage; 1 pt was investigator-assessed as CR after 18 wks (negative PET-CT and tumour-marker negative). CLDN6 CAR T cells ± CLDN6 CARVac had a manageable safety profile in this first-in-human trial, with encouraging signs of clinical activity in pts with limited treatment options.