![]() ![]() ![]() MM cells predominantly localize in the bone marrow (BM), and the development and accumulation of MM in the BM is supported by a BM microenvironment replete in factors that specifically promote the expansion of MM cells and facilitate escape from immunosurveillance ( 10– 12). However, several clinical trials have also observed non-responders and relapses despite the persistent expression of BCMA on MM cells ( 4, 8, 9), an indication that failure with CAR T-cell therapy may also potentially occur as a result of insufficient expansion, lack of persistence, or loss of efficacy of CAR T-cells. A number of relapses after treatment with B-cell maturation antigen (BCMA) CAR T-cells have been attributed to the downregulation of BCMA on MM cells and/or the emergence of BCMA negative MM clones ( 4– 7). Most clinical studies to date have reported relapses and/or non-responders. However, while CAR T-cell therapy has resulted in high overall response rates in patients with RRMM, the durability of the responses has been limited ( 1– 3). The advent of immunotherapies, including CAR T-cell therapy, has improved the prognosis of patients with relapsed/refractory multiple myeloma (RRMM) ( 1). In summary, the armored B2ARM CAR T cells mediate superior persistence, proliferation, multi-functionality, effector differentiation and anti-tumor function in pre-clinical models of multiple myeloma, while abrogating TGF-β-mediated suppression.ĭespite the recent surge in the development of novel therapeutics, multiple myeloma (MM), a hematologic disorder characterized by malignant proliferation of plasma cells, remains incurable. In NSG RPMI-8226 xenograft model in which tumors were additionally supplemented with TGF-β injections on days -1 through 11 of CAR T treatment, the B2ARM CAR T cells rejected tumors faster than the non-armored B2 CARs, and showed greater numbers of CD3+ and CD3+CAR+, central memory (CD45RO+CD62L+) and effector memory (CD45RO+CD62L-) T cells in the peripheral blood 18 days after treatment. In NSG mice bearing RPMI-8226 tumors overexpressing TGF-β, the B2ARM CAR mediated 100% tumor rejection and survival, superior infiltration of tumors on day 7 post CAR T treatment (%CD3+CAR+), and greater expression of IFN-γ, TNF-α, Ki67, Granzyme B, and PD-1, as compared to tumor-infiltrating non-armored B2 CAR T-cells. ![]() In addition, the B2ARM CAR T-cells, but not the conventional B2 CAR T-cells, resisted the TGF-β-mediated suppression of activation (CD25), exhaustion (PD-1, LAG3), and differentiation to T effectors (CD45RA+ CD45RO-CD62L-). Concordantly, after long-term exposure to targets in the presence of TGF-β, the B2ARM CAR T cells were enriched for Granzyme B, CD107a, Ki67 and polyfunctional cells T-cells (double or triple-positive for IFN-γ, IL-2 and/or TNF-α), as determined by flow cytometry. The B2ARM CAR T cells eliminated MM.1S multiple myeloma targets in long-term cytotoxicity assays, even under TGF-β-high conditions, whereas cytotoxic function of the non-armored B2 CAR -T cells was inhibited by TGF-β. The armored B2ARM CAR T cells, co-expressing BCMA targeting CAR with TGF-β dominant-negative receptor II, were generated by lentiviral transduction of primary human CD4+ and CD8+ T cells. We hypothesized that BCMA CAR T-cells armored to resist the suppressive effects of TGF-β will provide an advantage in treating multiple myeloma. ![]() Transforming growth factor beta (TGF-β) is a multifunctional cytokine abundantly expressed in the multiple myeloma bone marrow niche, where it promotes an immunosuppressive tumor microenvironment. Research and Development, Lentigen, a Miltenyi Biotec Company, Gaithersburg, MD, United StatesĬAR T-cell therapies targeting the B-cell maturation antigen eliminate tumors in relapsed/refractory multiple myeloma patients, however durable remissions remain difficult to attain.Alabanza, Ying Xiong, Bang Vu, Brian Webster †, Darong Wu, Peirong Hu, Zhongyu Zhu, Boro Dropulic †, Pradyot Dash and Dina Schneider * ![]()
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