Design\nof a Tumor Binding GMCSF as Intratumoral Immunotherapy\nof Solid Tumors

Abstract

Next-generation cancer immunotherapies may utilize immunostimulants\nto selectively activate the host immune system against tumor cells.\nCheckpoint inhibitors (CPIs) like anti-PD1/PDL-1 that inhibit immunosuppression\nhave shown unprecedented success but are only effective in the 20-30%\nof patients that possess an already “hot” (immunogenic)\ntumor. In this regard, intratumoral (IT) injection of immunostimulants\nis a promising approach since they can work synergistically with CPIs\nto overcome the resistance to immunotherapies by inducing immune stimulation\nin the tumor. One such immunostimulant is granulocyte macrophage-colony-stimulating\nfactor (GMCSF) that functions by recruiting and activating antigen-presenting\ncells (dendritic cells) in the tumor, thereby initiating anti-tumor\nimmune responses. However, key problems with GMCSF are lack of efficacy\nand the risk of systemic toxicity caused by the leakage of GMCSF from\nthe tumor tissue. We have designed tumor-retentive versions of GMCSF\nthat are safe yet potent immunostimulants for the local treatment\nof solid tumors. The engineered GMCSFs (eGMCSF) were synthesized by\nrecombinantly fusing tumor-ECM (extracellular matrix) binding peptides\nto GMCSF. The eGMCSFs exhibited enhanced tumor binding and potent\nimmunological activity in vitro and in vivo. Upon IT administration,\nthe tumor-retentive eGMCSFs persisted in the tumor, thereby alleviating\nsystemic toxicity, and elicited localized immune activation to effectively\nturn an unresponsive immunologically “cold” tumor “hot”.