H3.3-K27M neoantigen vaccine elicits anti-tumor T cell immunity against diffuse intrinsic pontine glioma: The phase I ENACTING trial.

Abstract

2052 Background: Diffuse intrinsic pontine glioma (DIPG) harboring H3.3-K27M mutation is a malignant pediatric brain tumor with a >90% mortality rate within two-year of diagnosis. Current therapeutic options for DIPG are limited. Aiming to improve therapeutic outcomes, we herein report the preliminary findings of a phase I trial studying a neoantigen peptide vaccine targeting H3.3-K27M. Methods: ENACTING is an open-label, single center, two-armed phase 1 trial to assess the safety and T cell immunity of a neoantigen peptide vaccine against H3.3-K27M. Patients aged ≥ 5 years old with newly diagnosed DIPG were consented and screened. HLA-A*02+/H3.3-K27M+ patients were enrolled to a two-arm study: Arm A consists of subjects receiving open debulking surgery, and Arm B consists of subjects without surgery eligibilities who received stereotactic biopsy. All patients subsequently received conformal radiotherapy and neoantigen vaccine treatment designed to elicit both CD4+ and CD8+ T cell immune response. Vaccine was administered intramuscularly in combination with polyinosinic-polycytidylic acid-poly-L-Iysine carboxymethylcellulose (Poly-ICLC). The primary objective is to evaluate the safety (AEs graded by CTCAE v4.03) and survival outcomes. Secondary objectives include maximum tolerated dose (MTD) and immunological responses. Results: As of Jan 2023, 11 patients have been treated, with 7 in Arm A and 4 in Arm B. No grade 3-4 treatment-related adverse events have been observed, with fever (81.9%) and injection site pain (54.5%) being the most common AEs. Among 10 efficacy-assessable patients, median progression-free survival (mPFS) and median overall survival (mOS) were 11.4 months (95% CI: 5.8~14.7) and 15.4 months (95% CI: 7.53~not reached), respectively. One-year OS rate was 66.7% (95% CI: 42~100%). One patient was assessed as complete response (CR). T cell responses against neoantigen were detected and H3.3-K27M mutation-specific CD4+ and CD8+ TCR clones were validated. Conclusions: The H3.3-K27M neoantigen vaccine was well tolerated. Initial results from this ongoing study suggest that, compared with other current therapies against DIPG, H3.3-K27M peptide vaccination may provide superior patient survival outcomes. Clinical trial information: NCT04749641 . [Table: see text]

Current immunotherapeutic approaches to diffuse intrinsic pontine glioma

“…As the hallmark mutation in DIPG, many therapeutic developments have also focused on H3K27M-targetted therapies. This includes the use of H3K27M antigen vaccines (NCT04749641) ( Zhang et al, 2023 ), CAR-T cells ( Wang et al, 2023b ), and combination therapies with immune checkpoint blockades (NCT02960230) ( Grassl et al, 2023 ). Preliminary data from the NCT04749641 trial testing H3K27M antigen vaccines indicates that survival may be improved compared to other therapies ( Zhang et al, 2023 ).…”

“…This includes the use of H3K27M antigen vaccines (NCT04749641) ( Zhang et al, 2023 ), CAR-T cells ( Wang et al, 2023b ), and combination therapies with immune checkpoint blockades (NCT02960230) ( Grassl et al, 2023 ). Preliminary data from the NCT04749641 trial testing H3K27M antigen vaccines indicates that survival may be improved compared to other therapies ( Zhang et al, 2023 ). Anti-H3.3K27M CAR-T cells that are specific to HLA-A∗02:01 have recently been developed ( Wang et al, 2023b ).…”