Triggering anti-GBM immune response with EGFR-mediated photoimmunotherapy

Abstract

Background Surgical resection followed by chemo-radiation postpones glioblastoma (GBM) progression and extends patient survival, but these tumours eventually recur. Multimodal treatment plans combining intraoperative techniques that maximise tumour excision with therapies aiming to remodel the immunologically cold GBM microenvironment could improve patients’ outcomes. Herein, we report that targeted photoimmunotherapy (PIT) not only helps to define tumour location and margins but additionally promotes activation of anti-GBM T cell response. Methods EGFR-specific affibody molecule (ZEGFR:03115) was conjugated to IR700. The response to ZEGFR:03115-IR700-PIT was investigated in vitro and in vivo in GBM cell lines and xenograft model. To determine the tumour-specific immune response post-PIT, a syngeneic GBM model was used. Results In vitro findings confirmed the ability of ZEGFR:03115-IR700 to produce reactive oxygen species upon light irradiation. ZEGFR:03115-IR700-PIT promoted immunogenic cell death that triggered the release of damage-associated molecular patterns (DAMPs) (calreticulin, ATP, HSP70/90, and HMGB1) into the medium, leading to dendritic cell maturation. In vivo, therapeutic response to light-activated conjugate was observed in brain tumours as early as 1 h post-irradiation. Staining of the brain sections showed reduced cell proliferation, tumour necrosis, and microhaemorrhage within PIT-treated tumours that corroborated MRI T2*w acquisitions. Additionally, enhanced immunological response post-PIT resulted in the attraction and activation of T cells in mice bearing murine GBM brain tumours. Conclusions Our data underline the potential of ZEGFR:03115-IR700 to accurately visualise EGFR-positive brain tumours and to destroy tumour cells post-conjugate irradiation turning an immunosuppressive tumour environment into an immune-vulnerable one.

Classification related to immunogenic cell death predicts prognosis, immune microenvironment characteristics, and response to immunotherapy in lower-grade gliomas

“…The immuno-inhibitory microenvironment is a leading contributor to immunotherapeutic tolerance in glioma ( 33 ). Glioma therapy induces ICD, which remodels the tumor immune microenvironment ( 34 , 35 ) and activates the immune system against carcinoma in immunocompetent patients. Therefore, we identified two ICD subclasses of patients through consensus clustering.…”

Targeted therapies for cancer

“…Specifically, in this study, the authors developed a novel EGFR-specific affibody molecule, which was conjugated to the photosensitizer dye IR700. This molecule enabled the authors to target EGFR in preclinical models of glioblastoma (GBM) [ 6 ]. More intriguingly, it showed that this EGFR-targeted photoimmunotherapy exhibited a promising anti-tumor effect in GBM by turning an immune-cold microenvironment into an immune-hot microenvironment.…”

A carbon dot-doped Cu-MOF-based smart nanoplatform for enhanced immune checkpoint blockade therapy and synergistic multimodal cancer therapy

“…In PDT, exogenous laser activates oxygen molecules to transform into highly cytotoxic singlet oxygen ( 1 O 2 ) to a Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of kill cancer cells. [16][17][18] However, severe hypoxia and glutathione (GSH) overexpression in the tumor microenvironment (TME) severely limit the efficacy of PDT. Therefore, improving the PDT effect becomes critical to triggering the host immune system.…”