Lukas Bunse

Adoptive cell therapies using chimeric antigen receptor or T cell receptor-transgenic T cells (TCR-T) are effective in treating hematological malignancies but have limited efficacy in solid tumors, particularly brain tumors. A major challenge of adoptive T cell therapy in brain tumors is lack of access to the target antigen, which is necessary for restimulation and persistence. Here, we addressed this challenge by using an mRNA vaccine encoding the cognate antigen to induce in vivo restimulation of transferred TCR-T cells in glioma models. Delivery of mRNA encoding the immunodominant MHC class I ovalbumin epitope SIINFEKL to splenic dendritic cells initiated strong expansion of adoptively transferred ovalbumin-specific OT1 CD8+ T cells to up to 80% of all circulating CD8+ T cells. RNA vaccination markedly improved T cell infiltration and retained interferon-stimulated gene signature in the brain, suppressing glioblastoma growth. The therapeutic efficacy of this approach was further demonstrated in an experimental model for a first-in-class TCR-T cell therapy targeting an HLA-A2-restricted immunodominant epitope of the human glioblastoma stemness antigen PTPRZ1. Co-administration of human dendritic cells transfected with PTPRZ1-mRNA led to rejection of orthotopically implanted primary human gliomas endogenously expressing PTPRZ1 and HLA-A2 after adoptive transfer of PTPRZ1-TCR-T cells. In summary, these findings indicate that mRNA vaccines can boost TCR-T cell therapy against glioblastoma.

The clonal glioma driver mutation IDH1 ^R132H gives rise to a major histocompatibility class II-restricted neoepitope. A multicenter, first-in-human phase 1 trial met its prespecified primary endpoints by demonstrating safety and immunogenicity of an IDH1-R132H peptide vaccine (IDH1-vac) integrated into standard of care in 33 participants with newly diagnosed grade III and IV (World Health Organization classification 2007) IDH1-R132H ⁺ astrocytomas (NOA16). Here we report on the clinical and immunological long-term follow-up of this trial as secondary and translational endpoints. The 8-year progression-free and overall survival (OS) rates were 0.42 months (confidence interval (CI): 0.24–0.59) and 0.66 months (CI: 0.46–0.79), respectively. For participants with grade IV astrocytoma, median OS was 106.1 months (CI: 39.6–not estimable (NE)), comparing favorably to the published median OS in this population ranging from 31.6–56.4 months. Within the responder group, sustained antibody responses to IDH1-R132H were associated with a favorable long-term clinical course. IDH1-vac-induced T cell responses were detected in the inflamed brain lesion of an IDH1-vac-associated pseudoprogression, whereas no IDH1-vac-induced T cells were found in participants with early progressive disease. The favorable long-term outcome of the NOA16 cohort supports investigating IDH1-vac in persons with newly diagnosed grade 3 and 4 (World Health Organization classification 2021) IDH -mutant astrocytomas in a randomized phase 2 trial (ClinicalTrials.gov identifier: NCT02454634 ).

Leptomeningeal metastatic disease (LMD) of solid tumors represents a cancer stage with high unmet therapeutic need. Here we report results from the dose escalation part of a multicenter phase 1 trial investigating intraventricular nivolumab, now continuing in the expansion part. Eligible participants had LMD from tumors with an approval for intraveneous PD1/PDL1 therapy or high tumor mutational burden. The primary endpoint was safety across four dose levels (20, 30, 40 and 50 mg) with each cohort reviewed by an independent data safety monitoring board before escalation. The secondary endpoint was overall survival. Exploratory endpoints included participant-reported outcome measures. Of 30 enrolled participants, 24 received at least one dose (intention-to-treat population) and 18 completed predefined safety evaluations (per-protocol population). One dose-limiting toxicity occurred at 40 mg. The primary endpoint was met and the recommended fixed dose for the ongoing expansion part is 50 mg. Median overall survival (OS) was 6.6 months. The 6-month, 12-month and 18-month OS rates were 55.0% (95% confidence interval (CI): 37.5–80.6%), 33.3% (95% CI: 17.8–62.4%) and 16.7% (95% CI 6.03–46.1%), respectively. Participant-reported quality of life remained stable. Intraventricular nivolumab has demonstrated safety and feasibility (ClinicalTrials.gov: NCT05112549 ).

Background: Replication repair deficiency is associated with increased risk of developing malignant gliomas. The aim of this study was to investigate primary mismatch repair deficient gliomas (PMMRDGs), a group of IDH-wildtype and H3-wildtype gliomas that is enriched among patients with CMMRD and Lynch syndrome. Methods: We investigated how PMMRDGs differ from other gliomas with respect to DNA methylation profile, genomic alterations, histopathology, and clinical outcomes. Results: PMMRDGs occur in pediatric, adolescents and the elderly, falling in two related methylation clusters and are characterized by a high frequency of replication repair deficiency. Histology showed multinucleated giant cells, and immunohistochemistry demonstrated loss of MMR protein expression. Survival analysis revealed long-term survival in patients with high mutational burden (>50 mut/Mb) and an intact chromosome 9p region, which was validated in an independent reference cohort. Conclusions: Overall, our findings indicate that PMMRDGs represent a distinct type of IDH-wildtype gliomas with potential for long-term survival likely driven by immune activation.

The type of cell death has proven to play a crucial role in cancer immunotherapy efficacy. Immunogenic cell death (ICD) enhances tumor adjuvanticity and antigenicity by releasing danger signals and altering the immune peptidome. The immunogenicity of ferroptosis, an iron-dependent form of cell death, remains uncertain. Here, we show that dendritic cell (DC) vaccines loaded with ferroptotic lysates protect mice against glioma growth, inducing IFN-γ production, and promoting robust CD8⁺ T cell infiltration, activation, and effector memory formation in the tumor microenvironment. The intrinsic immunogenicity of ferroptosis was independent of the glioma type and the ferroptosis inducer. Instead, it critically required the presence of the damage-associated molecular patterns calreticulin and ATP, rather than involving HMGB1–TLR4 signaling. However, supplementing these DAMPs into DC vaccines loaded with non-ICD lysates did not restore efficacy to the level of the ferroptosis-based DC vaccine, suggesting a more complex mechanism beyond a purely DAMP-mediated effect. These findings demonstrate that ferroptosis-loaded DC vaccines elicit a potent, tumor-specific immune response, capable of eradicating intracranial gliomas in mice, which highlights their potential in cancer immunotherapy.

Amyloid beta (Aβ) plaque deposition in the central nervous system (CNS) is a hallmark of Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA), triggering robust innate immune responses. However, the role of the adaptive immune system remains less well understood. Here we show the immune microenvironment dynamics in APP23 transgenic (APP23-tg) mice modelling CNS amyloid pathology, using single-cell transcriptomics. We observed a marked increase in T-cell populations during late disease stages, particularly CD8⁺ T-cells that clustered around Aβ plaques, suggesting a targeted immune response. Among these, we identified an Aβ plaque-associated subset of CD8⁺ T cells expressing interferon-stimulated genes (ISGs), which promoted Type-I interferon signaling. This subset also produced CXCL10, facilitating the recruitment of non-ISG T cells through the CXCL10-CXCR3 axis. Importantly, similar Type-I interferon responses were detected near plaques in human CNS amyloid pathology. Together, these findings highlight a shift from microglia-driven to T-cell-mediated neuroinflammation as amyloid pathology progresses, with implications for time-resolved therapy development.

Table S3. Primer for single cell T cell receptor sequencing.

Table S2. Murine primers for evaluation of Cic expression.