A Costimulatory CAR Improves TCR-based Cancer Immunotherapy.

Details

Serval ID
serval:BIB_78535A53B294
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A Costimulatory CAR Improves TCR-based Cancer Immunotherapy.
Journal
Cancer immunology research
Author(s)
Omer B., Cardenas M.G., Pfeiffer T., Daum R., Huynh M., Sharma S., Nouraee N., Xie C., Tat C., Perconti S., Van Pelt S., Scherer L., DeRenzo C., Shum T., Gottschalk S., Arber C., Rooney C.M.
ISSN
2326-6074 (Electronic)
ISSN-L
2326-6066
Publication state
Published
Issued date
01/04/2022
Peer-reviewed
Oui
Volume
10
Number
4
Pages
512-524
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
T-cell receptors (TCR) recognize intracellular and extracellular cancer antigens, allowing T cells to target many tumor antigens. To sustain proliferation and persistence, T cells require not only signaling through the TCR (signal 1), but also costimulatory (signal 2) and cytokine (signal 3) signaling. Because most cancer cells lack costimulatory molecules, TCR engagement at the tumor site results in incomplete T-cell activation and transient antitumor effects. To overcome this lack of signal 2, we genetically modified tumor-specific T cells with a costimulatory chimeric antigen receptor (CoCAR). Like classical CARs, CoCARs combine the antigen-binding domain of an antibody with costimulatory endodomains to trigger T-cell proliferation, but CoCARs lack the cytotoxic CD3ζ chain to avoid toxicity to normal tissues. We first tested a CD19-targeting CoCAR in combination with an HLA-A*02:01-restricted, survivin-specific transgenic TCR (sTCR) in serial cocultures with leukemia cells coexpressing the cognate peptide-HLA complex (signal 1) and CD19 (signal 2). The CoCAR enabled sTCR+ T cells to kill tumors over a median of four additional tumor challenges. CoCAR activity depended on CD19 but was maintained in tumors with heterogeneous CD19 expression. In a murine tumor model, sTCR+CoCAR+ T cells improved tumor control and prolonged survival compared with sTCR+ T cells. We further evaluated the CoCAR in Epstein-Barr virus-specific T cells (EBVST). CoCAR-expressing EBVSTs expanded more rapidly than nontransduced EBVSTs and delayed tumor progression in an EBV+ murine lymphoma model. Overall, we demonstrated that the CoCAR can increase the activity of T cells expressing both native and transgenic TCRs and enhance antitumor responses.
Keywords
Animals, Epstein-Barr Virus Infections, Herpesvirus 4, Human, Immunotherapy, Immunotherapy, Adoptive/methods, Mice, Neoplasms/therapy, Receptors, Antigen, T-Cell/genetics, Receptors, Chimeric Antigen/genetics
Pubmed
Web of science
Open Access
Yes
Create date
01/03/2022 12:39
Last modification date
15/07/2022 6:35
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