Antagonism of Endothelin Receptor B (ETRB) increases intratumoral T cell homing to tumors and enables tumor response to otherwise ineffective immunotherapy
In spite of generating a tangible antitumor cellular immune response in peripheral blood, tumor vaccines have proven largely ineffective for treatment of solid tumors. The success of immune therapy partly depends on the ability of effector cells to infiltrate tumors which in turn is dependent on tumor microenvironment.
T cell trafficking through lymphoid organs and peripheral tissues is tightly controlled through endothelial addressing signals regulating homing, adhesion and transendothelial migration. Endothelium provides a barrier that prevents T cell infiltration, and thus, there is a need for new pharmacologic intervention to improve cancer immunotherapy without increasing systemic inflammation.
Dr. Coukos and his team at Penn have developed methods of treating and enhancing efficacy of immunotherapy for a solid tumor by modulating the expression or activity of effector proteins such as ETRB, ET-1, ICAM-1 to guide T-cells to the tumor cells. They have shown that ETBR signaling blocks T cell adhesion to endothelium and ETBR blockade restored adhesion of T cells in vitro and markedly increased T cell homing to tumors. In addition, the endothelial molecular signature which includes ETBR, could assist in the selection of patients for whom ETBR blockade may enhance immunotherapy.
Increase in anti-tumor immune response
Adjuvant therapy to tumor vaccines
Stage of Development:
In vivo data