Details

Autor(en) / Beteiligte

• Hwang, Michael S.
• Miller, Michelle S.
• Thirawatananond, Puchong
• Douglass, Jacqueline
• Wright, Katharine M.
• Hsiue, Emily Han-Chung
• Mog, Brian J.
• Aytenfisu, Tihitina Y.
• Murphy, Michael B.
• Aitana Azurmendi, P.
• Skora, Andrew D.
• Pearlman, Alexander H.
• Paul, Suman
• DiNapoli, Sarah R.
• Konig, Maximilian F.
• Bettegowda, Chetan
• Pardoll, Drew M.
• Papadopoulos, Nickolas
• Kinzler, Kenneth W.
• Vogelstein, Bert
• Zhou, Shibin
• Gabelli, Sandra B.

Titel

Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens

Ist Teil von

• Nature communications, 2021-09, Vol.12 (1), p.5271-5271, Article 5271

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2021

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Chimeric antigen receptor (CAR) T cells have emerged as a promising class of therapeutic agents, generating remarkable responses in the clinic for a subset of human cancers. One major challenge precluding the wider implementation of CAR therapy is the paucity of tumor-specific antigens. Here, we describe the development of a CAR targeting the tumor-specific isocitrate dehydrogenase 2 (IDH2) with R140Q mutation presented on the cell surface in complex with a common human leukocyte antigen allele, HLA-B*07:02. Engineering of the hinge domain of the CAR, as well as crystal structure-guided optimization of the IDH2 R140Q -HLA-B*07:02-targeting moiety, enhances the sensitivity and specificity of CARs to enable targeting of this HLA-restricted neoantigen. This approach thus holds promise for the development and optimization of immunotherapies specific to other cancer driver mutations that are difficult to target by conventional means. Chimeric antigen receptor T cells in the clinic currently target cell-type-specific extracellular antigens on malignant cells. Here, authors engineer tumor-specific chimeric antigen receptor T cells that target human leukocyte antigen-presented neoantigens derived from mutant intracellular proteins.