Targeting cancer-associated fibroblasts in the bone marrow prevents resistance to CART-cell therapy in multiple myeloma.

Autor:	Sakemura R; T Cell Engineering.; Division of Hematology., Hefazi M; T Cell Engineering.; Division of Hematology., Siegler EL; T Cell Engineering.; Division of Hematology., Cox MJ; T Cell Engineering.; Division of Hematology., Larson DP; Division of Hematopathology., Hansen MJ; Department of Immunology., Manriquez Roman C; T Cell Engineering.; Division of Hematology.; Mayo Clinic Graduate School of Biomedical Sciences.; Department of Molecular Medicine., Schick KJ; T Cell Engineering.; Division of Hematology.; Mayo Clinic Graduate School of Biomedical Sciences.; Department of Molecular Pharmacology and Experimental Therapeutics, and., Can I; T Cell Engineering.; Division of Hematology.; Mayo Clinic Graduate School of Biomedical Sciences., Tapper EE; T Cell Engineering.; Division of Hematology., Horvei P; T Cell Engineering., Adada MM; T Cell Engineering.; Division of Hematology., Bezerra ED; T Cell Engineering.; Division of Hematology., Kankeu Fonkoua LA; T Cell Engineering.; Division of Hematology., Ruff MW; T Cell Engineering.; Department of Neurology, Mayo Clinic, Rochester, MN; and., Nevala WK; Department of Immunology., Walters DK; Department of Immunology., Parikh SA; Division of Hematology., Lin Y; Division of Hematology., Jelinek DF; Department of Immunology., Kay NE; Division of Hematology., Bergsagel PL; Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ., Kenderian SS; T Cell Engineering.; Division of Hematology.; Department of Immunology.; Department of Molecular Medicine.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2022 Jun 30; Vol. 139 (26), pp. 3708-3721.
DOI:	10.1182/blood.2021012811
Abstrakt:	Pivotal clinical trials of B-cell maturation antigen-targeted chimeric antigen receptor T (CART)-cell therapy in patients with relapsed/refractory multiple myeloma (MM) resulted in remarkable initial responses, which led to a recent US Food and Drug Administration approval. Despite the success of this therapy, durable remissions continue to be low, and the predominant mechanism of resistance is loss of CART cells and inhibition by the tumor microenvironment (TME). MM is characterized by an immunosuppressive TME with an abundance of cancer-associated fibroblasts (CAFs). Using MM models, we studied the impact of CAFs on CART-cell efficacy and developed strategies to overcome CART-cell inhibition. We showed that CAFs inhibit CART-cell antitumor activity and promote MM progression. CAFs express molecules such as fibroblast activation protein and signaling lymphocyte activation molecule family-7, which are attractive immunotherapy targets. To overcome CAF-induced CART-cell inhibition, CART cells were generated targeting both MM cells and CAFs. This dual-targeting CART-cell strategy significantly improved the effector functions of CART cells. We show for the first time that dual targeting of both malignant plasma cells and the CAFs within the TME is a novel strategy to overcome resistance to CART-cell therapy in MM. (© 2022 by The American Society of Hematology.)
Databáze:	MEDLINE
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