Dual targeting ovarian cancer by Muc16 CAR T cells secreting a bispecific T cell engager antibody for an intracellular tumor antigen WT1 Journal Article

   

Authors:	Mun, S. S.; Meyerberg, J.; Peraro, L.; Korontsvit, T.; Gardner, T.; Malviya, M.; Kyi, C.; O’Cearbhaill, R. E.; Liu, C.; Dao, T.; Scheinberg, D. A.
Article Title:	Dual targeting ovarian cancer by Muc16 CAR T cells secreting a bispecific T cell engager antibody for an intracellular tumor antigen WT1
Abstract:	Epithelial ovarian cancer is the most lethal of gynecological cancers. The therapeutic efficacy of chimeric antigen receptor (CAR) T cell directed against single antigens is limited by the heterogeneous target antigen expression in epithelial ovarian tumors. To overcome this limitation, we describe an engineered cell with both dual targeting and orthogonal cytotoxic modalities directed against two tumor antigens that are highly expressed on ovarian cancer cells: cell surface Muc16 and intracellular WT1. Muc16-specific CAR T cells (4H11) were engineered to secrete a bispecific T cell engager (BiTE) constructed from a TCR mimic antibody (ESK1) reactive with the WT1-derived epitope RMFPNAPYL (RMF) presented by HLA-A2 molecules. The secreted ESK1 BiTE recruited and redirected other T cells to WT1 on the tumor cells. We show that ESK1 BiTE-secreting 4H11 CAR T cells exhibited enhanced anticancer activity against cancer cells with low Muc16 expression, compared to 4H11 CAR T cells alone, both in vitro and in mouse tumor models. Dual orthogonal cytotoxic modalities with different specificities targeting both surface and intracellular tumor-associated antigens present a promising strategy to overcome resistance to CAR T cell therapy in epithelial ovarian cancer and other cancers. © 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Keywords:	controlled study; nonhuman; t lymphocyte; mouse; ovary cancer; gene expression; animal experiment; animal model; antineoplastic activity; in vitro study; cancer resistance; t lymphocyte receptor; cancer cell; ovary carcinoma; ca 125 antigen; wt1 protein; hla a antigen; wt1; female; article; chimeric antigen receptor t-cell immunotherapy; dual targeting; esk1 bite; muc16 car t cells; tcr mimic mab
Journal Title:	Cancer Immunology, Immunotherapy
Volume:	72
Issue:	11
ISSN:	0340-7004
Publisher:	Springer
Date Published:	2023-11-01
Start Page:	3773
End Page:	3786
Language:	English
DOI:	10.1007/s00262-023-03529-w
PUBMED:	37635172
PROVIDER:	scopus
PMCID:	PMC10991175
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85169132534&doi=10.1007%2fs00262-023-03529-w&partnerID=40&md5=d70f15ce4c2f5178bb247e26d3f58838
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in PubMed and PDF -- Corresponding author is MSK author: David A. Scheinberg -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/210645