Targeting Cancer-Associated Fibroblasts in the Bone Marrow Prevents Resistance to CART-Cell Therapy in Multiple Myeloma

• Published in: Blood Vol. 139; no. 26; pp. 3708 - 3721
• Main Authors: Sakemura, Reona, Hefazi, Mehrdad, Siegler, Elizabeth L., Cox, Michelle J., Larson, Daniel P., Hansen, Michael J., Roman, Claudia Manriquez, Schick, Kendall J, Can, Ismail, Tapper, Erin E., Horvei, Paulina, Adada, Mohamad M., Bezerra, Evandro D., Fonkoua, Lionel Aurelien Kankeu, Ruff, Michael W., Nevala, Wendy K., Walters, Denise K., Parikh, Sameer A., Lin, Yi, Jelinek, Diane F., Kay, Neil E., Bergsagel, P. Leif, Kenderian, Saad S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30-06-2022; The American Society of Hematology
• Subjects: Bone Marrow; Cancer-Associated Fibroblasts - pathology; Cell- and Tissue-Based Therapy; Fibroblasts; Humans; Immunobiology and Immunotherapy; Immunotherapy, Adoptive - methods; Multiple Myeloma - pathology; Tumor Microenvironment
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2021012811

Pivotal clinical trials of B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory multiple myeloma (MM) resulted in remarkable initial responses, which led to a recent FDA approval. Despite their success, 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 demonstrated that CAFs inhibit CART-cell anti-tumor activityand promote MM progression. CAFs express molecules such as fibroblast activation protein and SLAMF7, which are attractive immunotherapy targets. To overcome CAF-induced CART-cell inhibition, we generated CART cells targeting both MM cells and CAFs. Our dual-targeting CART-cell strategy significantly improved the effector functions of CART cells. We demonstrate for the first time that dual targeting both malignant plasma cells and the CAFs within the TME is a novel strategy to overcome resistance to CART-cell therapy in MM.