Glioblastoma (GBM) is one of the most common primary malignant brain tumors in adults with a very aggressive clinical presentation. Treatment is also very challenging because its pathological mechanisms are among the most complex in brain tumors. Surgical options for glioblastoma have changed little over the past 30 years, and the 5-year survival rate for patients is only around 5%.
Currently, neurosurgical treatments for the disease aim to maximize tumor resection while avoiding additional nerve damage. Clinicians typically treat patients with glioblastoma and other brain tumors using a photodynamic therapy called 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery. The therapy uses light-sensitive drugs to help identify tumor cells that need to be removed during surgery, but because tumors grow in sensitive areas of the brain, such as the motor cortex, which is involved in planning and controlling voluntary movements. Therefore, surgery may still leave residual tumor. This means that cancer may recur at any time in the future; moreover, immunosuppressive cells within the tumor microenvironment (TME) also render immunotherapy ineffective.
Therefore, there is an urgent need to improve surgical methods for glioblastoma to help prolong patient survival. Recently, the Institute of Cancer Research (ICR) preclinical molecular imaging team used a new technology called photoimmunotherapy (PIT) on the basis of photodynamic therapy (PDT) to immunologically activate the tumor microenvironment. , turning "cold" tumors into "hot", thereby promoting the response of glioblastoma to immunotherapy.
Photoimmunotherapy (PIT) is a light-mediated treatment in which photosensitizers are synergistically enhanced with highly specific monoclonal antibodies (mAbs), antibody fragments, or affibody molecules that precisely bind to specific targets The body's immune response. EGFR, a glycoprotein that is a receptor for epidermal growth factor (EGF) cell proliferation and signaling, has been found to be mutated in many cases of glioblastoma.
Based on the high expression rate and oncogenicity of EGFR, the researchers hypothesized that targeting this receptor with photoimmunotherapy could promote activation of CD8+ T cell attraction and overcome the immune "cold" state of glioblastoma. In this study, they combined an EGFR-specific affinity molecule (ZEGFR:03115) with a fluorescent molecule used in surgery, IR700, to form a conjugate -- ZEGFR:03115-IR700.
Shining light on ZEGFR:03115-IR700 caused the photosensitizer to glow to highlight microscopic areas of residual tumor in the brain; switching to near-infrared light triggered antitumor activity that killed tumor cells. In vitro results confirmed that ZEGFR:03115-IR700 has the ability to generate reactive oxygen species (ROS) under light exposure, promote immunogenic cell death, trigger the release of damage-related molecules into the culture medium, and lead to dendritic cell maturation.
The researchers then tested the therapy in a mouse model implanted with glioblastoma. ZEGFR:03115-IR700 can trigger a local immune response in the brain tumor microenvironment as soon as 1 hour of irradiation. Conjugates bound to EGFR on glioblastoma cell membranes induce receptor expression-dependent cell death upon near-infrared light irradiation, in part due to the production of reactive oxygen species.
Staining of brain sections showed reduced cell proliferation, tumor necrosis, and microbleeds in photoimmunotherapy-treated tumors. This effectively confirmed the acute response of the tumor to the therapy. Compared to untreated controls, mice treated with ZEGFR:03115-IR700 had higher levels of CD4+ and CD8+ immune cells, brain scans also showed clear signs of tumor cell death, and the compound resulted in eradication of residual tumor cells.
These data suggest that ZEGFR:03115-IR700 triggers an immune response in vivo that allows immune cells to target cancer cells. Therefore, this therapy helps prevent the recurrence of malignant glioma cells after surgery.
Brain tumors like glioblastoma are difficult to treat, and patients have too few treatment options. Surgery is very challenging due to the specificity of the tumor location, so new therapies that observe tumor cells to be removed during surgery and treat residual cancer cells after surgery may be of great benefit to patients.
In addition to potentially being a future treatment for glioblastoma, photoimmunotherapy could also be used to treat other types of cancer through the use of new affibosome molecules. Currently, the research team is also studying the treatment of childhood neuroblastoma.
In conclusion, this study highlights the potential of ZEGFR:03115-IR700 in the treatment of glioblastoma by accurately observing EGFR-positive brain tumors and destroying tumor cells after combined irradiation, changing the immunosuppressive tumor microenvironment to immune fragile environment, thus giving this therapy greater potential for the treatment of aggressive brain tumors.