Effects of Interferon-α-2a on Th3 Cytokine Response in Multiple Myeloma Patients

Sönmez, Mehmet; Sönmez, Bircan; Eren, Necmi; Yılmaz, Mustafa; Karti, S.; Ovalı, Ercüment

doi:10.1177/030089160409000404

Cited by 4 publications

(3 citation statements)

References 21 publications

(5 reference statements)

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“…Several studies supported that myeloma tumor cells in MM, the most common disease type in monoclonal gammopathies, evaded the immune system and could induce immunosuppression by producing immunoregulatory factors such as TGFβ1 (25). Myeloma cells increase Th3 cytokine response by secreting TGFβ1, which causes defective Th1 and Th2 cytokine responses, therefore a significant suppression of the immune system is seen (26). TGFβ1 is present in the bone marrow (BM) environment and constitutes a pivotal molecule controlling BM cell proliferation and differentiation (27).…”

Section: Discussionmentioning

confidence: 99%

Laboratory Characterizations on 2007 Cases of Monoclonal Gammopathies in East China

Wang

Gao

et al. 2008

Cell Mol Immunol

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Section: Discussionmentioning

confidence: 99%

Laboratory Characterizations on 2007 Cases of Monoclonal Gammopathies in East China

Wang

Gao

et al. 2008

Cell Mol Immunol

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“…In those patients that responded favorably to fludarabine, IFNex sigsificantly prolonged the duration of remission from disease. Finally, some data suggest that IFN-ex may reverse tumor-induced immunosuppression, as evidenced by the enhanced production of interleukin-2 (IL-2) by multiple myeloma patients treated with IFN-ex-2a (23). Recent investigations have demonstrated that IFN-ex can be used in combination with BCNU clinically to induce antitumor outcomes.…”

Section: Discussionmentioning

confidence: 99%

The Role of Interferon-α in a Successful Murine Tumor Therapy

Steele

Hauser

2005

Exp Biol Med (Maywood)

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Combination therapy using reovirus type 3 and the chemo-therapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) is sufficient to cure approximately 80% of EL-4 lymphoma tumor-bearing BD2F1 male mice. Cured animals can be challenged with the EL-4 tumor, in the absence of the therapy, to yield 100% survival, whereas those challenged with heterologous tumor produce 0% survival. These results strongly suggest that a host-immune response is responsible for the observed therapeutic effect. Reovirus, a double-stranded RNA virus, is an efficient inducer of type I interferon. In an effort to determine the role of virus in this therapy, we substituted interferon-alpha (IFN-alpha) for reovirus in the therapy. Doses of IFN-alpha from 1000-10,000 U were capable of replacing reovirus to produce cure rates similar to reovirus. Spleen cells isolated from therapy-treated animals demonstrated high levels of cytotoxicity against the natural killer cell-sensitive cell line YAC-1, but not against EL-4 tumor. In vitro stimulation of isolated spleen cells by IFN-alpha resulted in a high level of natural killer cell activity, but no cytotoxicity against the EL-4 tumor. A significant antiproliferative effect against the EL-4 tumor in cell culture was demonstrated by IFN-alpha. Finally, therapy-treated, tumor-bearing mice that were injected with anti-IFN-alpha + -beta antibodies had similar survival levels as control mice, indicating that other cytokines might also play a role in promoting tumor killing. These investigations suggest that IFN-alpha may be a mediator of antitumor activity in the reovirus therapy system.

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“…A number of studies have noted elevated levels of TGF-b in the BM and peripheral blood of MM patients (34)(35)(36)(37). Several studies have additionally reported that there is a discernable impairment in the functionality of immune cells from MM patients, including T-cell dysfunction (38)(39)(40).…”

Section: Introductionmentioning

confidence: 99%

Armored BCMA CAR T Cells Eliminate Multiple Myeloma and Are Resistant to the Suppressive Effects of TGF-β

Alabanza

Xiong

et al. 2022

Front. Immunol.

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CAR T-cell therapies targeting the B-cell maturation antigen eliminate tumors in relapsed/refractory multiple myeloma patients, however durable remissions remain difficult to attain. 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. We hypothesized that BCMA CAR T-cells armored to resist the suppressive effects of TGF-β will provide an advantage in treating multiple myeloma. 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. 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. 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. 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-). 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 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 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.

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Effects of Interferon-α-2a on Th3 Cytokine Response in Multiple Myeloma Patients

Abstract: These findings suggest IFN-alpha-2a may enhance nonTh3 cytokine responses in multiple myeloma patients.

Cited by 4 publications

References 21 publications

Laboratory Characterizations on 2007 Cases of Monoclonal Gammopathies in East China

Laboratory Characterizations on 2007 Cases of Monoclonal Gammopathies in East China

The Role of Interferon-α in a Successful Murine Tumor Therapy

Armored BCMA CAR T Cells Eliminate Multiple Myeloma and Are Resistant to the Suppressive Effects of TGF-β

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