Abstract B037: Banana Lectin expressing CAR T cells to target Pancreatic Cancer

Abstract

Abstract To overcome both the heterogenous and dynamic expression of tumor antigen expression in pancreatic ductal adenocarcinoma (PDAC) and the physical barrier provided by the associated fibrotic stroma, we have developed a novel therapy that recognizes and binds to distinct patterns of aberrant glycosylation specifically expressed on tumor cells and their surrounding stroma. Aberrant glycosylation patterns are a hallmark of cancer and are widely present on tumors including PDAC. We therefore incorporated H84T BanLec as part of a chimeric antigen receptor and co-expressed the construct in T cells and showed that H84T BanLec CAR expressing T-cells can effectively target pancreatic tumors. We hypothesized that our novel lectin CAR would enhance the activity of T cells when co-expressed with conventional scFV – derived CARs targeting tumor associated antigens We compared the activity of dual-expressing H84T/HER.2 CAR-T or H84T/PSMA CAR-T cells against single- expressing CARs targeting PDAC. We determined anti-tumor cytotoxicity by measuring residual GFP+ tumor cells in a sequential killing assay using flow cytometry. We observed superior anti-tumor activity using dual expressing CAR T cells compared to T cells expressing either HER.2- or H84T- or PSMA- CAR alone. Similarly, in 3D multicellular spheroids containing tumor and cancer-supportive stromal cells, an IncuCyte live imaging assay shows dual CAR T cells have greater cytotoxicity against PDAC than single CAR expressing T cells (p= 0.02 H84T/HER.2 vs HER.2 CAR; p=0.00003 H84T/PSMA CAR vs PSMA CAR). These results also translate to improved anti- tumor function of dual CAR T cells in PDAC xenograft in vivo models where H84T/HER.2 CAR T cells significantly reduced the tumor volume burden (p=0.015; H84T/HER.2 average=57.1mm3; HER.2 average=116.1mm3; H84T average=130.3mm3). These findings suggest that H84T BanLec CAR T cells provide a tool to target the aberrant glycosylation patterns of malignant cells and their supporting stroma and may contribute to an effective treatment option for PDAC patients. We are now elucidating the underlying mechanism by which H84T BanLec CARs enhance tumor activity and promote T cell infiltration. Citation Format: Katie McKenna, Ada I Ozcan, David Markovitz, Malcolm K Brenner. Banana Lectin expressing CAR T cells to target Pancreatic Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B037.