Year: 2021
Type: preprint
Abstract: ABSTRACT The lack of highly tumor-specific antigens limits the development of engineered T cell therapeutics because of life-threatening “on-target/off-tumor” toxicities. Here we identify ALPPL2 as a tumor-specific antigen expressed in a spectrum of solid tumors, including mesothelioma. ALPPL2 can act as a sole target for chimeric antigen receptor (CAR) therapy or be combined with tumor-associated antigens such as MCAM or mesothelin in synthetic Notch (synNotch) CAR combinatorial antigen circuits. SynNotch CAR T cells display superior tumor control when compared to CAR T cells to the same antigens by prevention of CAR-mediated tonic signaling allowing T cells to maintain a long-lived memory and non-exhausted phenotype. Collectively, we establish ALPPL2 as a clinically viable target for multiple solid tumors and demonstrate the multi-faceted therapeutic benefits of synNotch CAR T cells. ONE SENTENCE SUMMARY SynNotch CAR circuits targeting novel solid tumor antigens enhance specificity and improve therapeutic efficacy by regulating T cell exhaustion.
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, Parker Institute for Cancer Immunotherapy, Cancer Research UK, Svenska Sällskapet för Medicinsk Forskning, Vetenskapsrådet, National Institutes of Health, University of California, San Francisco, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco
OpenAlex ID: W3119249954