O-09.03 Preliminary immunogenicity results from the dose escalation phase of a first-in-human study of the mRNA-based cancer vaccine CVGBM in patients with newly diagnosed MGMT-unmethylated glioblastoma

<h3>Background</h3> The investigational therapeutic mRNA-based vaccine, CVGBM, encodes five class 1 and three class 2 segments derived from tumor-associated antigens (TAAs) with potential relevance in glioblastoma (GBM). Here, we present results from an ongoing, first-in-human study evaluating the safety and immunogenicity of CVGBM in patients with newly-diagnosed and surgically resected <i>MGMT</i>-unmethylated GBM. <h3>Materials and Methods</h3> Eligible patients were HLA-A*02:01-positive and had newly-diagnosed <i>MGMT</i>-unmethylated GBM (CNS WHO Grade 4) with a gross total or partial resection and completed radiotherapy with or without concomitant temozolomide. The study consists of a dose escalation and a dose expansion part. Patients received intramuscular injections of CVGBM on Days 1, 8, 15, 29, 43, 57 and 71 (main treatment period) plus six optional doses at 6-week intervals (maintenance period). Primary endpoints are safety, tolerability and dose-limiting toxicities (DLTs), whereas immunogenicity is an exploratory endpoint. Blood samples for assessment of cell-mediated immunity by interferon-y ELISPOT were collected on days 1, 43, 71, 78, 99, and 181 (Day 181 only if the patient did not receive maintenance treatment) and for assessment of serum cytokines and chemokines on days 1, 2, 8, 43, 44, 71, 72, and 78. <h3>Results</h3> 16 patients have been enrolled in the dose escalation part (three patients each received 12 µg, 25 µg, 50 µg, and seven received 100 µg of mRNA, respectively). All patients completed the 2-week DLT evaluation period without DLTs, and 100 µg was selected as the recommended dose for trial expansion based on safety data from all cohorts. The most common treatment emergent AEs were short-lived chills, pyrexia, headache and fatigue mostly of mild to moderate severity. Seven patients experienced Grade 3 AEs after the DLT period, assessed as potentially treatment related to CVGBM by investigators and evenly distributed across dose cohorts. CVGBM vaccine induced immunogenicity was mainly <i>de novo</i> and observed in 77% of evaluable patients, in which 67% showed an antigen-specific T cell immune response to multiple TAAs. Innate immune cytokines were also transiently induced upon vaccination. <h3>Conclusions</h3> CVGBM was generally well tolerated up to a dose level of 100 µg and was able to induce antigen-specific T-cell responses in the vast majority of patients. <b>L.L. de Freitas Chama:</b> A. Employment (full or part-time); Significant; CureVac SE. <b>P. Romer Roche:</b> A. Employment (full or part-time); Significant; CureVac SE. <b>G. Tabatabai:</b> None. <b>P. Freres:</b> None. <b>P. Hau:</b> None. <b>M. Glas:</b> None. <b>C. Seidel:</b> None. <b>L. von Baumgarten:</b> None. <b>M.C. Burger:</b> C. Other Research Support (supplies, equipment, receipt of drugs or other in-kind support); Modest; Boehringer Ingelheim. <b>M. van den Bent:</b> None. <b>M. Falk:</b> A. Employment (full or part-time); Significant; CureVac SE. <b>P. Kelemen:</b> A. Employment (full or part-time); Significant; CureVac SE. <b>F. Schwenke:</b> A. Employment (full or part-time); Significant; CureVac SE. <b>J. Hess:</b> A. Employment (full or part-time); Significant; CureVac SE. <b>B. Srivastava:</b> A. Employment (full or part-time); Significant; CureVac SE. <b>T. Seibel:</b> A. Employment (full or part-time); Significant; CureVac SE. <b>S.D. Koch:</b> A. Employment (full or part-time); Significant; CureVac SE. <b>U. Gnad-Vogt:</b> A. Employment (full or part-time); Significant; CureVac SE.