@article{f4f0f1ec1ae243dcb7a5dbb2dcb25e39,
title = "Targeting cancer-associated fibroblasts in the bone marrow prevents resistance to CART-cell therapy in multiple myeloma",
abstract = "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.",
author = "Reona Sakemura and Mehrdad Hefazi and Siegler, {Elizabeth L.} and Cox, {Michelle J.} and Larson, {Daniel P.} and Hansen, {Michael J.} and {Manriquez Roman}, Claudia and Schick, {Kendall J.} and Ismail Can and Tapper, {Erin E.} and Paulina Horvei and Adada, {Mohamad M.} and Bezerra, {Evandro D.} and {Kankeu Fonkoua}, {Lionel Aurelien} and Ruff, {Michael W.} and Nevala, {Wendy K.} and Walters, {Denise K.} and Parikh, {Sameer A.} and Yi Lin and Jelinek, {Diane F.} and Kay, {Neil E.} and Bergsagel, {P. Leif} and Kenderian, {Saad S.}",
note = "Funding Information: Conflict-of-interest disclosure: S.S.K. is an inventor on patents in the field of CAR immunotherapy that are licensed to Novartis (through an agreement between Mayo Clinic, University of Pennsylvania, and Novartis). R.S., M.J.C., and S.S.K. are inventors on patents in the field of CAR immunotherapy that are licensed to Humanigen (through Mayo Clinic). S.S.K. and M.H. are inventors on patents in the field of CAR immunotherapy that are licensed to Mettaforge (through Mayo Clinic). S.S.K. receives research funding from Kite, Gilead, Juno, Celgene, Novartis, Humanigen, MorphoSys, Tolero, Sunesis, and Lentigen. N.E.K. receives research funding from Acerta Pharma, Bristol Myers Squibb, Celgene, Pharmacyclics, Tolero Pharmaceuticals, MEI Pharma, Sunesis, and AbbVie; is a member of the Data Safety Monitoring Committee for Agios Pharm, AstraZeneca, Celgene, CytomX Therapeutics, MorphoSys, and Rigel; and is an advisory board member for CytomX Therapy, Pharmacyclics, Dava Oncology, Juno Therapeutics, AstraZeneca, and Oncotracker. Y.L. receives research funding from Janssen, Takeda, Merck, Kite, and Celgene/BMS; is a member of the Data Safety Monitoring Committee for Sorrento; and has participated in advisory board meetings of Kite, Gilead, Janssen, Bristol Myers Squibb, Celgene, JUNO, bluebird bio, Legend Biotech, and Gamida Cell (she was not personally compensated for her participation). S.A.P. receives research funding from Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma; and has participated in advisory board meetings of Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie (he was not personally compensated for his participation). The remaining authors declare no competing financial interests. Funding Information: This work was supported through grants from Mayo Clinic Multiple Myeloma SPORE P50CA186781 (R.S.) and K12CA090628 (S.S.K.), the Mayo Clinic Cancer Center (S.S.K.), the Mayo Clinic K2R pipeline (S.S.K.), the National Comprehensive Cancer Network (S.S.K.), the Mayo Clinic Center for Individualized Medicine (S.S.K.), the Predolin Foundation (R.S. and S.S.K.), the Exact Foundation (S.S.K.), the Eagles Foundation (R.S.), and the Lu Foundation (Y.L. and S.S.K.). Publisher Copyright: {\textcopyright} 2022 American Society of Hematology",
year = "2022",
month = jun,
day = "30",
doi = "10.1182/blood.2021012811",
language = "English (US)",
volume = "139",
pages = "3708--3721",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "26",
}