Safety
DLTs, impaired bone marrow function, toxicity, treatment-emergent adverse, toxicities, CRS, RNA-LPX cancer vaccine platformTransient, cytopenia, headache, deaths, pancytopenia, Cancer
ADVERSE EVENT, DISEASE PROGRESSION, ADVERSE EVENT, CYTOPENIA, IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME, PANCYTOPENIA, CANCER
All 22 patients treated within the study were included in the safety analysis. The data cutoff date was 6 October 2022, with a median follow-up of five months (range: 29–416 days, Extended Data Table Nineteen of 22 patients had treatment-emergent adverse events (TEAEs) greater than or equal to grade (G) 3 (Extended Data Table TEAEsAEs graded for severity using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.5.0, with CRS graded according to American Society for Transplantation and Cellular Therapy consensus gradingTEAE is defined as any adverse event (AE) with an onset date on or after the first administration of CLDN6 CAR-T (if the AE was absent before the first administration of CLDN6 CAR-T) or that worsened after the first administration of CLDN6 CAR-T (if the AE was present before the first administration of CLDN6 CAR-T). AEs with an onset date more than 90 days after the last administration of any investigational medicinal product (IMP) were considered as treatment-emergent if assessed as related to any IMP by the investigator.CRS was seen in ten patients (46%), eight of whom were treated at DL2 (Extended Data Table One patient treated at DL1 plus CARVac had symptoms (headache and decreased level of alertness) classified as G1 immune effector cell-associated neurotoxicity syndrome (ICANS) that occurred in conjunction with G2 CRS and resolved spontaneously within 24 h (Extended Data Table Dose-limiting toxicities (DLTs) emerged in two patients treated at DL2, one with monotherapy and one in combination with CARVac (Extended Data Table The other DLT was prolonged G4 pancytopenia observed in a heavily pretreated GCT patient reported 21 days post-ACT. The patient was nonresponsive to granulocyte colony-stimulating factor, received an autologous peripheral blood stem cell support on day 32, upon which the patient’s bone marrow function recovered within 14 days. The patient was redosed with CAR-T cells 41 weeks after the first CAR-T cell administration. This DLT experience led to the decision to consider GCT patients who had recently undergone HDCT as at risk for treatment-related persistent cytopenia. Consequently, we introduced protocol amendments to make the availability of autologous peripheral blood stem cells a prerequisite for treatment of patients with HDCT within the last 12 months or with impaired bone marrow function with the full dose of LD. Alternatively, we allowed dose-reduced LD.No further DLTs were observed after enrollment of three additional patients into each of these two DL2 cohorts. The Safety Review Committee (SRC) determined that the MTD (primary endpoint) was not reached. The recommended phase 2 dose of CLDN6 CAR-T cells was not further pursued as enrollment to the planned DL3 cohorts was canceled per the study protocol amendment to facilitate a repeat of the CAR-T dose escalation component with CAR-T cells manufactured with an automated process, including potential testing of higher dose levels. All eight deaths in the study were classified as disease progression and not attributed to CAR-T cell toxicity.The safety profile of CARVac was in line with previous reports related to our RNA-LPX cancer vaccine platformTransient release of IFNγ and IFNγ inducible protein 10, peaking 3–6 h post intravenous CARVac administration, was observed in serum cytokine measurements (Extended Data Fig. In summary, the safety profile of both dose levels of CLDN6 CAR-T cells as monotherapy or in combination with CARVac was manageable (Table 