In vivo effects of Adoptive T-cell Immunotherapy against a novel antigen in Glioblastoma
2Tel Aviv Sourasky Medical Center, Tel Aviv, and Department of Immunology, Weizmann Institute of Science, Israel
3Laboratory of Cancer Biology, Institute of Biomedicine, Centre of Excellence for Translational Medicine, University of Tartu, Estonia
4Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, USA
5Center for Nanomedicine and Department of Cell, Molecular and Developmental Biology, University of California Santa Barbara, USA
6Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Spain
7Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Spain
8Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, Denmark
9Sagol School of Neuroscience, Tel Aviv University, Israel
Malignant gliomas are the most common primary brain tumors and glioblastoma is considered one of the most aggressive malignancies in adult and pediatric patients. Despite decades of research no curative treatment is available and it thus remains associated with a very dismal prognosis.
Although recent pre-clinical and clinical studies have demonstrated the feasibility of chimeric antigen receptors (CAR) T cell immunotherapeutic approach in glioblastoma, tumor heterogeneity and lack of tumor-specific antigens remain among the most important challenges to be addressed.
We identified p32/gC1qR/HABP/C1qBP to be specifically expressed on the surface of glioma cells, making it an attractive tumor associated antigen for redirected CAR T cell therapy. We generated p32 CAR T cells and found them to recognize and specifically eliminate murine and human p32 expressing glioma cells and tumor derived endothelial cells in vitro. The antitumor efficacy of this CAR was evaluated in a syngeneic mouse GBM model and in human xenograft models, showing in both models a significant survival extension, tumor shrinkage and on-target effect in the treated groups. Confocal microscopy analysis of tumor sections, showed reduced blood vessels (vWF staining) in the p32-CART treated group, supporting the potential anti-angiogenic effect of these CARs. Treatment with our CAR T cells showed no signs of toxicity.
Collectively, our studies identified a previously uncharacterized biomarker, p32, that holds potential for serving as a novel CAR target with a dual function for cancer immunotherapy in gliomas.