A novel nanoparticle treatment for glioblastoma has been developed by Northwestern Medicine investigators, as per research published in Nature Communications.
Maciej Lesniak, MD, chair and the Michael J. Marchese Professor of Neurosurgery, was senior author of the study published in Nature Communications. Image Credit: Northwestern University
Glioblastoma is one of the most complex and common types of primary brain cancer, which are lethal and treatment-resistant cancers, as per the National Brain Tumor Society. For several years, the five-year survival rate for glioblastoma patients hangs near 7% and has stayed unchanged.
Earlier Northwestern Medicine research has revealed that glioblastoma tumors add large numbers of immunosuppressive tumor-associated myeloid cells (TAMCs), impairing the ability of the immune system to fight the tumor and minimizing the efficacy of chemotherapy and radiation.
Immunosuppression is a hallmark of the tumor microenvironment. TAMCs are a key driver of immunosuppression and therapy resistance. Because TAMCs compose 30 to 50 percent of the brain tumor mass, there’s an urgent need to develop new therapeutic strategies to target and modulate those immunosuppressive cells in brain tumors.
Peng Zhang, Ph.D., Study First Author and Assistant Professor, Neurological Surgery, Northwestern University
In the existing study, investigators focused on cultured TAMCs with a nanoparticle they built to offer dimeric amidobenzimidazole, or diABZI, a newly developed synthetic compound, targetting a protein called stimulator of interferon genes, or STING. Also, the nanoparticle was loaded with antibodies targeting CD47 and PD-L1, which are two immune checkpoint proteins that are overexpressed in TAMCs and glioblastoma tumors following radiotherapy.
As per the research, the TAMCs that received the therapy generated decidedly fewer immunosuppressive proteins and augmented immunostimulatory proteins.
When nanoparticles were used to treat mice with glioblastoma, researchers noticed a spike in the number of activated T-cells, which are typically accountable for mounting an immune response against the tumor but are generally lacking in brain tumors. As per the study, the treated mice’s T-cells infiltrated the tumor in larger numbers and prolonged the lifecycle of the mice.
In around 70% of the animals, tumors were eradicated after nanoparticle treatment and radiation therapy, which is a standard treatment for glioblastoma.
Overcoming tumor immunosuppression is key to designing effective immunotherapeutic strategies. This approach opens the way for modulating the tumor microenvironment in such a way as to enhance the potential of immunotherapy.
Maciej Lesniak, MD, Senior Study Author and Chair and the Michael J. Marchese Professor, Neurosurgery, Northwestern University
Then, investigators replicated the experiment with the use of blood and tumor samples from glioblastoma patients and once again observed the reprogrammed TAMCs and activated anti-tumor T-cells.
The findings indicate that nanoparticle therapy could be a successful way to complement already present care and amplify immune responses in glioblastoma, Lesniak stated.
Lesniak, Zhang, and their co-workers believe in bringing nanoparticle therapy to clinical trials, Zhang stated.
We also would like to gain more insight into how the host immune response could contribute to the therapy efficacy or therapy resistance of those tumors. We also want to incorporate the immune metabolism and bioinformatics into our multi-disciplinary research so we can do a thorough job regarding the design of the next generation of therapeutics against brain tumors.
Peng Zhang, Ph.D., Study First Author and Assistant Professor, Neurological Surgery, Northwestern University
Lesniak and Zhang are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
The study was funded by the National Institutes of Health/National Cancer Institute grant R37CA266487 and Northwestern Brain Tumor SPORE P50CA221747.
Journal Reference
Zhang, P. et al. (2019). Therapeutic targeting of tumor-associated myeloid cells synergizes with radiation therapy for glioblastoma. Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.1906346116