510. Treating Epithelial and Metastatic Malignancies with Glycoform-Specific Chimeric Antigen Receptors
Year: 2016
Type: article
Abstract: Cancer-specific glycosylation deficiencies generating Tn or sTn O-linked glycans are found in >80% of the most lethal cancers (lung, prostate, breast, colon, ovary, pancreas). These hypoglycosylated cancer glycoantigens decrease cell-cell interactions and increase the mobility and metastatic potential of tumor cells. We developed a CAR specific to the Tn/sTn antigen of the oncogene Mucin-1 (MUC1), which is highly upregulated in many epithelial cancers and is heavily O- and N-glycosylated. Our CAR uses the scFv sequence derived from the 5E5 mAb and the endodomains of CD3zeta and 4-1BB that promote T cell activation and co-stimulation, respectively. We have shown that the 5E5 mAb and the 5E5 CAR are specific to the cancer-specific glycoform of MUC1 but not normal MUC1 through in vitro binding and cytokine assays and that the 5E5 CAR is non-reactive to normal human primary cells. We demonstrated that the 5E5 CAR T cells are responsive to ovarian, breast, lung, pancreatic, and leukemia cancers and developed NSG mouse xenograft models using Jurkat leukemia cell line and Hs766T metastatic pancreatic cell line that show rapid clearance of established tumors by 5E5 CAR T cells and prolonged survival of tumor-bearing mice. Restoring normal glycosylation in Jurkat leukemia cells abolishes the expression of the hypoglycosylated form of Muc1 and also prevents 5E5 CAR T cell cytotoxicity, further highlighting the specificity of the 5E5 CAR for the cancer-specific glycoform of MUC1. Infusion of human MUC1-transgenic mice with murine 5E5 CAR T cells showed an exquisite safety profile, while infusion of normal glycoform MUC1-specific murine CAR T cells (HMFG1 CAR, a previously described MUC1-specific CAR) demonstrate extreme safety concerns. These results demonstrate that targeting the cancer-specific glycoform of MUC1 provides a safe, yet potent cancer-specific immunotherapy for treating most epithelial malignancies and holds the potential to eradicate metastatic disease.
Source: Molecular Therapy
Authors: Avery D. Posey, Alina Boestaneau, Laura A. Johnson, Carl H. June
Institution: University of Pennsylvania
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W2565234993