Biology subjects

Burger, M. C.

Publications and source records attributed to Burger, M. C..

3 recordsLinked to original sources

bioRxiv2025

Engineered AAV9 as in vivo gene delivery platform for the selective transduction of TME cell subsets

Precise in vivo gene delivery to specific cell types remains a significant challenge in gene therapy, particularly for cancer immunotherapy applications. Here, we rationally engineered AAV9 to become a modular, receptor-targeted vector for selective in vivo gene delivery. We first identified the N272A and W503A mutations as effective in ablating the native tropism of AAV9. Subsequently, designed ankyrin repeat proteins (DARPins) were inserted into the GH2/3 capsid loop, redirecting vector specificity towards defined cellular receptors without compromising capsid integrity or yield. As a proof of concept, HER2-targeted DART-AAV9 vectors demonstrated highly selective transduction of HER2-positive tumor cells in vitro and in vivo, in both, subcutaneous and orthotopic glioblastoma models, with negligible transduction of off-target organs including liver, heart, and kidney. When equipped with immunomodulatory genes (anti-PD-1 or IL-2) HER2-DART-AAV9 mediated secretion of functional therapeutic proteins from transduced tumor cells. Additionally, our modular platform facilitated rapid generation of CD8-targeted DART-AAV9 vectors, enabling selective transduction of human CD8+ T cells. Importantly, the engineered vectors exhibited favorable resistance to neutralization by human serum and retained their specificity and potency in human blood, underscoring their potential for clinical translation. Together, these findings establish DART-AAV9 as a versatile, precise, and clinically promising gene delivery platform for cancer immunotherapy.

bioengineering↗

bioRxiv2024

Glioma-associated tertiary lymphoid structures are sites of lymphocyte clonal expansion and plasma cell formation

Adult-type diffuse gliomas, the most common primary brain tumors, pose significant clinical challenges due to limited treatment options, restricted anti-tumor immune response and dismal patient prognosis. In this study, we elucidate the immunological function and clinical relevance of intra-tumoral tertiary lymphoid structures (TLS) in adaptive anti-glioma immunity. We conducted a comprehensive, unbiased analysis of lymphoid aggregation in 642 gliomas using a multi-modal approach that combines RNA sequencing with spatial transcriptome and proteome profiling. Our findings reveal that TLS are present in 15% of tumors and correlate with improved overall survival. Gliomas with TLS exhibit a remodeled perivascular space, marked by transcriptional upregulation and spatial redistribution of collagens associated with barrier functions. Furthermore, we demonstrate that TLS maturation into sites of dynamic adaptive immune responses, characterized by clonal T and B cell expansion and IgA+ and IgG+ plasma-cell formation, is driven by efficient early T cell recruitment to the perivascular space.

immunology↗

bioRxiv2024

A Mimicry-Based Strategy Between Human and Commensal Antigens for the Development of a New Family of Immune Therapies for Cancer

Peptide vaccines have emerged as a promising strategy for cancer immunotherapy, yet often lack of strong, specific and sustained immune responses against tumor antigens. To achieve a robust immune response, the effective selection of tumour antigens is crucial. While neoantigens trigger potent immune responses, their use suffers from patient specificity and their rarity in low-mutational tumors. Alternatively, the immunogenic potential of tumor-associated antigens (TAAs) is limited by central immune tolerance. Molecular mimicry and T cell cross-reactivity is a proposed mechanism to trigger a robust T cell-mediated antitumor response. Although molecular mimicry between pathogens and tumor antigens has been described, the potential benefits of exploiting this molecular mimicry with commensal bacterial antigens in antitumor immunity have not been thoroughly investigated despite strong evidence that the composition of the human microbiota significantly influences immune competency. Our new approach called OncoMimics, which uses molecular mimicry between commensal bacterial and tumoral antigens to induce cross-reactive cytotoxic T cells against tumor cells. In preclinical studies, vaccination with OncoMimic peptides (OMPs) led to the expansion of CD8+ T cells reacting against homologous tumor-associated antigen peptides and elicits cytotoxic activity against tumor cells. OMPs are efficiently recognized by a prevalent T cell population within the peripheral blood mononuclear cells of healthy individuals. An ongoing clinical trial (NCT04116658) using OncoMimics in patients with glioblastoma demonstrates early, durable, and cross-reactive tumor antigen CD8+ T cell responses with pronounced memory persistence. By overcoming the current vaccine limitations, OncoMimics constitutes a promising strategy for enhancing cancer immunity and improving patient outcomes. Statement of SignificanceThis study introduces OncoMimics, a peptide-based immunotherapy leveraging molecular mimicry to induce robust, cross-reactive T cell responses against tumor antigens, showing promising early results in an ongoing glioblastoma clinical trial (NCT04116658)

immunology↗