Promotes T Cell Recruitment Against Gliomas Through Increased IL-8 Receptor Expression
These therapeutic T cells specifically target cancer cells expressing CD70 using modified receptors that bind to IL-8 proteins secreted by the tumors. Cancer currently holds the position as the second leading cause of death in the United States, and the CDC projects it to rise to the first by the year 2020. Gliomas, in particular, cause over 16,000 deaths each year and pose significant obstacles in treatment due to their critical locations in the brain or spinal cord. Chimeric antigen receptor (CAR) T cells demonstrate promising results for clinically targeting gliomas. However, available CAR-T cell immunotherapies can fail upon antigen escape, wherein the tumor cells cease to express the targeted antigen, leaving the T cells without a target. Furthermore, the immunosuppressive tumor microenvironment strongly hampers the ability of CAR-T cells to traffic to the tumor site. The immunosuppressive ligand CD70 is highly expressed by both primary and recurrent gliomas, presenting a consistent therapeutic target.
Researchers at the University of Florida have developed CD70-specific CAR-T cells that utilize IL-8 receptors to increase their efficiency in attacking tumors. The IL-8, secreted by gliomas when patients undergo standard radiation, attracts the corresponding receptors on the T cells, increasing T cell recruitment to the tumor site. This improved signaling combined with the consistent presence of CD70 targets enhances the anti-tumor efficacy of CAR-T cells, enabling them to surpass barriers that might limit their movement toward the tumor through the bloodstream.
Modified CAR-T cells that co-opt IL-8 released from radiation in malignant gliomas and other tumor types to enhance intratumor T-cell trafficking into tumor sites to maximize anti-tumor activity
- Contains IL-8 receptors, enhancing attraction of CAR-T cells to IL-8 secreting tumors
- Uses standard radiation therapy to increase IL-8 secretion from tumor site, making tumors a better target for IL-8 receptor modified CAR-T cells
- Focuses on CD70 proteins expressed in both primary and recurrent tumors, identifying a consistent target for immunotherapy
These CAR-T cells possess an augmented specificity for CD70 brain and spinal cord glioma tumors due to a modification that stimulates the expression of IL-8 receptors. Engineered T cells take on anti-tumor properties for distinct tumors, such as those expressing the CD70 protein, by grafting CARs onto them. While the CAR-T cells do not typically express IL-8 receptors, additional manipulations initiate this expression. When patients undergo radiation therapy, gliomas begin to secrete significant levels of IL-8 proteins. These proteins, known as chemokines, attract the modified CAR-T cells, which contain IL-8 receptors (CXCR1 or CXCR2). The IL-8 receptors target and then bind to the tumor cells, eliminating the glioma. These protein-mediated signaling interactions increase the targeted recruitment of IL-8 receptor modified CAR-T cells to the CD70 gliomas.