Therapeutic applications of toll-like receptors (TLRs) agonists in AML

Ye, Peng; Wang, Yanzhong; Lan, Jianping; Wang, Manling

doi:10.1007/s12094-022-02917-5

Cited by 4 publications

(3 citation statements)

References 90 publications

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“…R848 can activate the NK cells and result in accessory cell-dependent IFN-γ production [113]. A recent study on the therapeutic applications of TLR agonists in acute myeloid leukemia (AML) demonstrated that R848 has direct antileukemic effects and considerably impairs the growth of human AML cells in immunodeficient mice, suggesting that treatment with TLR8 agonists may be a promising new therapeutic strategy for AML [114].…”

Section: The Tlr7/8 Signaling Pathwaymentioning

confidence: 99%

Targeting toll-like receptor 7/8 for immunotherapy: recent advances and prospectives

Sun

Zhang

et al. 2022

Biomark Res

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Toll-like receptors (TLRs) are a large family of proteins that are expressed in immune cells and various tumor cells. TLR7/8 are located in the intracellular endosomes, participate in tumor immune surveillance and play different roles in tumor growth. Activation of TLRs 7 and 8 triggers induction of a Th1 type innate immune response in the highly sophisticated process of innate immunity signaling with the recent research advances involving the small molecule activation of TLR 7 and 8. The wide range of expression and clinical significance of TLR7/TLR8 in different kinds of cancers have been extensively explored. TLR7/TLR8 can be used as novel diagnostic biomarkers, progression and prognostic indicators, and immunotherapeutic targets for various tumors. Although the mechanism of action of TLR7/8 in cancer immunotherapy is still incomplete, TLRs on T cells are involved in the regulation of T cell function and serve as co-stimulatory molecules and activate T cell immunity. TLR agonists can activate T cell-mediated antitumor responses with both innate and adaptive immune responses to improve tumor therapy. Recently, novel drugs of TLR7 or TLR8 agonists with different scaffolds have been developed. These agonists lead to the induction of certain cytokines and chemokines that can be applied to the treatment of some diseases and can be used as good adjutants for vaccines. Furthermore, TLR7/8 agonists as potential therapeutics for tumor-targeted immunotherapy have been developed. In this review, we summarize the recent advances in the development of immunotherapy strategies targeting TLR7/8 in patients with various cancers and chronic hepatitis B.

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Section: The Tlr7/8 Signaling Pathwaymentioning

confidence: 99%

Targeting toll-like receptor 7/8 for immunotherapy: recent advances and prospectives

Sun

Zhang

et al. 2022

Biomark Res

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“…This field is less investigated in hematological malignancies. Nevertheless, several results demonstrated that TLR signaling increased the immunogenicity of AML cells as well, making them more vulnerable to T cell-mediated invasion [ 122 , 123 ]. For example, a study reported that TLR7/8 agonists could induce DC activation and IL-2 production consequently activating NK cells in AML patients [ 123 ].…”

Section: Immunotherapies Targeting the Innate Immune System In Amlmentioning

confidence: 99%

Targeting the innate immune system in pediatric and adult AML

Perzolli,

Koedijk,

Zwaan

et al. 2024

Leukemia

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While the introduction of T cell-based immunotherapies has improved outcomes in many cancer types, the development of immunotherapies for both adult and pediatric AML has been relatively slow and limited. In addition to the need to identify suitable target antigens, a better understanding of the immunosuppressive tumor microenvironment is necessary for the design of novel immunotherapy approaches. To date, most immune characterization studies in AML have focused on T cells, while innate immune lineages such as monocytes, granulocytes and natural killer (NK) cells, received less attention. In solid cancers, studies have shown that innate immune cells, such as macrophages, myeloid-derived suppressor cells and neutrophils are highly plastic and may differentiate into immunosuppressive cells depending on signals received in their microenvironment, while NK cells appear to be functionally impaired. Hence, an in-depth characterization of the innate immune compartment in the TME is urgently needed to guide the development of immunotherapeutic interventions for AML. In this review, we summarize the current knowledge on the innate immune compartment in AML, and we discuss how targeting its components may enhance T cell-based- and other immunotherapeutic approaches.

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“… 13 In other cancers, chemotherapy has been used in combination with immune-stimulating agents to encourage an immune response against tumor antigens released during cell death. 14 , 15 , 16 Several studies have explored adjuvants such as toll-like receptor (TLR) agonists, including poly(I:C) (TLR3), 17 LPS (TLR4), 18 R848 (TLR7/8), 19 CpG (TLR9), 20 and others, 21 for the treatment of leukemia. However, none of these have reached clinical utility, in part, due to ineffective delivery strategies that lead to reduced activity and systemic toxicity.…”

Section: Introductionmentioning

confidence: 99%

Cysteine-binding adjuvant enhances survival and promotes immune function in a murine model of acute myeloid leukemia

Slezak,

Chang,

Beckman

et al. 2024

Blood Advances

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Therapeutic vaccination has long been a promising avenue for cancer immunotherapy but is often limited by tumor heterogeneity. The genetic and molecular diversity between patients often results in variation in the antigens present on cancer cell surfaces. As a result, recent research has focused on personalized cancer vaccines. While promising, this strategy suffers from time-consuming production, high cost, inaccessibility, and targeting of a limited number of tumor antigens. Instead, we explore an antigen-agnostic polymeric in situ cancer vaccination platform for treating blood malignancies, in our model here with acute myeloid leukemia (AML). Rather than immunizing against specific antigens or targeting adjuvant to specific cell surface markers, this platform leverages a characteristic metabolic and enzymatic dysregulation in cancer cells that produces an excess of free cysteine thiols on their surfaces. These thiols increase in abundance after treatment with cytotoxic agents like cytarabine, the current standard of care in AML. The resulting free thiols can undergo efficient disulfide exchange with pyridyl disulfide (PDS) moieties on our construct and allow for in situ covalent attachment to cancer cell surfaces and debris. PDS-functionalized monomers are incorporated into a statistical co-polymer with pendant mannose groups and TLR7 agonists to target covalently linked antigen and adjuvant to antigen-presenting cells in the liver and spleen after intravenous administration. There, the compound initiates an anti-cancer immune response, including T cell activation and antibody generation, ultimately prolonging survival in cancer-bearing mice.

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Therapeutic applications of toll-like receptors (TLRs) agonists in AML

Cited by 4 publications

References 90 publications

Targeting toll-like receptor 7/8 for immunotherapy: recent advances and prospectives

Targeting toll-like receptor 7/8 for immunotherapy: recent advances and prospectives

Targeting the innate immune system in pediatric and adult AML

Cysteine-binding adjuvant enhances survival and promotes immune function in a murine model of acute myeloid leukemia

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