Data from Targeting GPC2 on Intraocular and CNS Metastatic Retinoblastomas with Local and Systemic Delivery of CAR T Cells

• DOI: 10.1158/1078-0432.c.7403506.v1
• Publication Date: 2024-08-15T07:29:49Z
• Authors: Guillem Pascual-P...; Brendan McIntyre; Anna M. Giudice; Fatemeh Alikarami; Amanda Morrissey; Stephanie Matlaga; Ted J. Hofmann; Victor Burgueño; Kyra Harvey; Daniel Martinez; Amish C. Shah; Jessica B. Foster; Jennifer Pogoriler; Ralph C. Eagle; Angel M. Carcaboso; Carol L. Shields; Ann-Marie Leahey; Kristopher R. Bosse
• Keywords: Retinoblastoma; Systemic administration

<div>AbstractPurpose:<p>Retinoblastoma is the most common intraocular malignancy in children. Although new chemotherapeutic approaches have improved ocular salvage rates, novel therapies are required for patients with refractory and metastatic disease. Chimeric antigen receptor (CAR) T cells targeting glypican-2 (GPC2) a potential therapeutic strategy.</p>Experimental Design:<p>GPC2 expression its regulation by E2F1 transcription factor were studied retinoblastoma patient samples cellular models. <i>In vitro</i>, we performed functional studies comparing GPC2 CAR different costimulatory domains (4-1BB CD28). vivo</i>, efficacy of local systemic administration was evaluated leptomeningeal human xenograft models.</p>Results:<p>Retinoblastoma tumors, but not healthy retinal tissues, expressed cell surface GPC2, this tumor-specific driven E2F1. GPC2-directed CARs 4-1BB costimulation (GPC2.BBz) superior to CD28 stimulatory (GPC2.28z), efficiently inducing cytotoxicity enhancing T-cell proliferation polyfunctionality. GPC2.BBz had enhanced persistence, which led significant tumor regression compared either control CD19 or GPC2.28z CARs. In models, trafficked tumor-bearing eyes after intravitreal infusions, significantly prolonging survival. central nervous system (CNS) intraventricular systemically administered activated retinoblastoma-involved CNS resulting robust substantially extended overall mouse survival.</p>Conclusions:<p>GPC2-directed effective against retinoblastomas.</p></div>