Kate Amato Foundation Awarded Projects

Project Description:

Retinoblastoma is a childhood cancer of the eye. Therapeutic strategies based on locally deliver
chemotherapy into the eye have improved ocular salvage rates; however, enucleation (or surgical
removal of the eye) is still required for those patients with refractory intraocular disease to prevent tumor dissemination outside the eye, which is fatal. To identify alternative treatments, we have recently shown that our own T-cells genetically modified to recognize retinoblastoma cell surface antigens are effective in mice with intraocular and metastatic retinoblastoma, but some tumors ultimately progress. Herein, we hypothesize that retinoblastoma cells secrete proteins in the tumor microenvironment that can lead to T-cell suppression. In this project, we will study how these retinoblastoma-secreted proteins both inhibit T-cell therapies and interact with the own retinoblastoma cells to lead tumor growth. Most importantly, we will further engineer T cells to both recognize retinoblastoma cell surface antigens and block these proteins secreted by the tumor cells that impair T-cell efficacy. To this end, we will introduce into the T-cells genetically modified receptors that will convert the T-cell suppressive properties of retinoblastoma-secreted proteins into T-cell activating signals. Overall, our project aims to understand the resistance mechanisms to T-cell-based therapies in retinoblastoma and use this knowledge to rationally design next-generation T-cell approaches with improved efficacy profiles.