The emerging role of anti‐<scp>CD</scp>25 directed therapies as both immune modulators and targeted agents in cancer

Flynn, Michael J.; Hartley, John A.

doi:10.1111/bjh.14770

Cited by 83 publications

(74 citation statements)

References 123 publications

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“…A highly immunosuppressive Treg subtype, expressing tumor-necrosis-factor-receptor 2 with activated NF-κB/p65 has been abundantly recognized in human ovarian cancers ( 52 ). In human hepatocellular carcinoma, the decreased survival rate was associated to a higher level of peripheral blood Tregs; similar observations have been reported in chronic lymphocytic leukemia (CLL) patients ( 53 ). However, controversial is the role of high Treg infiltration as a prognostic parameter in colorectal cancer ( 54 , 55 ).…”

Section: Nf-κb: a Forward Player Of Tregs Activity In Cancersupporting

confidence: 78%

Notch and NF-κB: Coach and Players of Regulatory T-Cell Response in Cancer

et al. 2018

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The Notch signaling pathway plays multiple roles in driving T-cell fate decisions, proliferation, and aberrant growth. NF-κB is a cell-context key player interconnected with Notch signaling either in physiological or in pathological conditions. This review focuses on how the multilayered crosstalk between different Notches and NF-κB subunits may converge on Foxp3 gene regulation and orchestrate CD4+ regulatory T (Treg) cell function, particularly in a tumor microenvironment. Notably, Treg cells may play a pivotal role in the inhibition of antitumor immune responses, possibly promoting tumor growth. A future challenge is represented by further dissection of both Notch and NF-κB pathways and consequences of their intersection in tumor-associated Treg biology. This may shed light on the molecular mechanisms regulating Treg cell expansion and migration to peripheral lymphoid organs thought to facilitate tumor development and still to be explored. In so doing, new opportunities for combined and/or more selective therapeutic approaches to improve anticancer immunity may be found.

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Section: Nf-κb: a Forward Player Of Tregs Activity In Cancersupporting

confidence: 78%

Notch and NF-κB: Coach and Players of Regulatory T-Cell Response in Cancer

et al. 2018

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“…It has been reported that, in malignant CD4 + T cells derived from the CTCL, both of activated PI3K/AKT and MEK/ERK pathways contribute to mTORC1 activation, which appears to depend on the IL‐2‐induced γc/Jak signalling . IL‐2R has proven to be an attractive target for immune intervention and T cell‐directed therapies . To date, the IL‐2R target agents, such as daclizumab, basiliximab and denileukin diftitox, have demonstrated activity in diseases characterized by proliferation of activated T cells, but most of them are mainly used to protect against the rejection of certain organ transplants or cannot block IL‐2 signalling activated by intermediate affinity binding .…”

Section: Introductionmentioning

confidence: 99%

“…15 IL-2R has proven to be an attractive target for immune intervention and T cell-directed therapies. 16 To date, the IL-2R target agents, such as daclizumab, basiliximab and denileukin diftitox, have demonstrated activity in diseases characterized by proliferation of activated T cells, but most of them are mainly used to protect against the rejection of certain organ transplants or cannot block IL-2 signalling activated by intermediate affinity binding. [17][18][19] Importantly, daclizumab and basiliximab are two monoclonal antibodies to human IL-2Rα and there is no related small molecule compound targeting IL-2R on the market.…”

Section: Introductionmentioning

confidence: 99%

TPD7 inhibits the growth of cutaneous T cell lymphoma H9 cell through regulating IL‐2R signalling pathway

Zhu

Liu

Shi

et al. 2019

J Cellular Molecular Medi

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IL‐2R pathway is a key regulator in the development of immune cells and has emerged as a promising drug target in cancer treatment, but there is a scarcity of related inhibitors. TPD7 is a novel biphenyl urea taspine derivate, which has been shown anti‐cancer effect. Here, we demonstrated the anti‐cancer activity of TPD7 in cutaneous T cell lymphoma and investigated the underlying mechanism of TPD7 through IL‐2R signalling. The inhibitory effect of TPD7 on cell viability exhibited a strong correlation with the expression level of IL‐2R, and cutaneous T cell lymphoma H9 and HUT78 cells were most sensitive to TPD7. TPD7 was nicely bound to IL‐2R and down‐regulated the mRNA and protein levels of IL‐2R. Furthermore, TPD7 suppressed the downstream cascades of IL‐2R including JAK/STAT, PI3K/AKT/mTOR and PLCγ/Raf/MAPK signalling, resulting in Bcl‐2 mitochondrial apoptosis pathway and cell cycle proteins CDK/Cyclins regulation. And, these were verified by flow cytometry analysis that TPD7 facilitated cell apoptosis in H9 cells via mitochondrial pathway and impeded cell cycle progression at G2/M phase. TPD7 is a novel anti‐cancer agent and may be a potential candidate for cutaneous T cell lymphoma treatment by regulating IL‐2R signalling pathway.

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“…ADCT-301 is the first ADC against CD25, a receptor for IL-2 often found on hematological tumors that has a role in prognosis and oncogenesis in these malignancies [ 30 ]. This molecule is being studied in a phase I clinical trial in patients with relapsed or refractory HD and NHL ( NCT02432235 ).…”

Section: Antibody Drug Conjugatesmentioning

confidence: 99%

Cancer immunotherapy beyond immune checkpoint inhibitors

et al. 2018

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Malignant cells have the capacity to rapidly grow exponentially and spread in part by suppressing, evading, and exploiting the host immune system. Immunotherapy is a form of oncologic treatment directed towards enhancing the host immune system against cancer. In recent years, manipulation of immune checkpoints or pathways has emerged as an important and effective form of immunotherapy. Agents that target cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1) are the most widely studied and recognized. Immunotherapy, however, extends beyond immune checkpoint therapy by using new molecules such as chimeric monoclonal antibodies and antibody drug conjugates that target malignant cells and promote their destruction. Genetically modified T cells expressing chimeric antigen receptors are able to recognize specific antigens on cancer cells and subsequently activate the immune system. Native or genetically modified viruses with oncolytic activity are of great interest as, besides destroying malignant cells, they can increase anti-tumor activity in response to the release of new antigens and danger signals as a result of infection and tumor cell lysis. Vaccines are also being explored, either in the form of autologous or allogenic tumor peptide antigens, genetically modified dendritic cells that express tumor peptides, or even in the use of RNA, DNA, bacteria, or virus as vectors of specific tumor markers. Most of these agents are yet under development, but they promise to be important options to boost the host immune system to control and eliminate malignancy. In this review, we have provided detailed discussion of different forms of immunotherapy agents other than checkpoint-modifying drugs. The specific focus of this manuscript is to include first-in-human phase I and phase I/II clinical trials intended to allow the identification of those drugs that most likely will continue to develop and possibly join the immunotherapeutic arsenal in a near future.

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The emerging role of anti‐CD25 directed therapies as both immune modulators and targeted agents in cancer

Cited by 83 publications

References 123 publications

Notch and NF-κB: Coach and Players of Regulatory T-Cell Response in Cancer

Notch and NF-κB: Coach and Players of Regulatory T-Cell Response in Cancer

TPD7 inhibits the growth of cutaneous T cell lymphoma H9 cell through regulating IL‐2R signalling pathway

Cancer immunotherapy beyond immune checkpoint inhibitors

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