Endoglin-Directed CAR T Cells Comprehensively Target Tumors in Advanced Sarcomas

Authors

Harrison R Berger
Malina Maharana
Jeneffer Mirabal
Lyazat Kurenbekova
Alberto Delaidelli
Atreyi Dasgupta
Ahmed Z Gad
Mohamed F Sheha
Sybrina S Kerr
Ada I Ozcan
Jessica S Morris
Angela M Major
M John Hicks
Mary K McKenna
Ben K Seon
Matthew L Baker
Poul H Sorensen
Meenakshi Hegde
Jason T Yustein
Nabil Ahmed
Sujith K Joseph

Publication Date

10-1-2025

Journal

Cancer Immunology Research

DOI

10.1158/2326-6066.CIR-24-0897

PMID

40748238

PMCID

PMC12492877

PubMedCentral® Posted Date

10-4-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

There are limited therapeutic options for patients with advanced sarcomas, which leads to dismal outcomes for children and adults. Although chimeric antigen receptor (CAR) T cells hold promise for treating advanced sarcomas, this approach is constrained by a paucity of effective targets. Our previous clinical study identified endoglin (ENG/CD105), a TGFβ coreceptor, as a target of the endogenous immune response in a patient with sarcoma who exhibited an exceptional response to HER2-targeted CAR T-cell therapy. ENG is expressed on various sarcomas, cancer-associated fibroblasts, and neoangiogenic vessels and therefore offers comprehensive tumor targeting. Furthermore, ENG knockout in sarcoma cells reduces their invasiveness, highlighting its potential as a therapeutic target. Accordingly, we designed a second-generation human ENG-targeting CAR molecule signaling through the CD28 endodomain and retrovirally transduced primary human T cells with this CAR. ENG CAR T cells exhibited strong antigen-specific cytokine release, robust proliferation, memory formation, and cytotoxic function against various sarcoma cell lines. Their cytotoxicity remained unaffected by the presence of soluble ENG or its natural ligand, bone morphogenetic protein-9. Furthermore, ENG CAR T cells disrupted multicellular tumor spheroids in vitro, overcoming tumor compactness and the stromal barrier created by cancer-associated fibroblasts, which are critical challenges in sarcoma CAR T-cell therapy. In orthotopic xenograft models of sarcomas, ENG CAR T-cell treatment resulted in control of tumor growth and metastasis, leading to survival extension. In summary, our study describes the involvement of ENG in sarcoma metastasis and validates our human ENG CAR T cells as a potential therapeutic for advanced sarcomas.

Keywords

Humans, Endoglin, Sarcoma, Animals, Immunotherapy, Adoptive, Mice, Receptors, Chimeric Antigen, Cell Line, Tumor, Xenograft Model Antitumor Assays, T-Lymphocytes, Female, Adoptive cell therapy; immunotherapy; endoglin (ENG, CD105); CAR-T cells; advanced sarcomas

Published Open-Access

yes

Recommended Citation

Berger, Harrison R; Maharana, Malina; Mirabal, Jeneffer; et al., "Endoglin-Directed CAR T Cells Comprehensively Target Tumors in Advanced Sarcomas" (2025). Faculty and Staff Publications. 5581.
https://digitalcommons.library.tmc.edu/baylor_docs/5581