TD-92, a novel erlotinib derivative, depletes tumor-associated macrophages in non-small cell lung cancer via down-regulation of CSF-1R and enhances the anti-tumor effects of anti-PD-1

Shih, Chi Ting; Shiau, Chung Wai; Chen, Yen‐Lin; Chen, Li Ju; Chao, Tzu I.; Wang, Cheng Yi; Huang, Chao Yuan; Hung, Ming-Hui; Chen, Kuen Feng

doi:10.1016/j.canlet.2020.10.043

Cited by 17 publications

(13 citation statements)

References 51 publications

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“…The mode of action of TD-92 is different from the above-mentioned CSF-1R inhibitors. It decreases the expression of CSF-1R, which results in the reduction of the number of TAMs [77]. Monoclonal antibodies targeting CSF-1R, like AMG820, LY3022855, emactuzumab, also entered Phase 1 of clinical trials and were well tolerated by patients with a range of advanced solid tumors (Table 1).…”

Section: Depletion Of Tams In the Tmementioning

confidence: 99%

The Role of Macrophages in Cancer Development and Therapy

Cendrowicz

Sas

Bremer

et al. 2021

Cancers

193

106

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Macrophages are critical mediators of tissue homeostasis and influence various aspects of immunity. Tumor-associated macrophages are one of the main cellular components of the tumor microenvironment. Depending on their activation status, macrophages can exert a dual influence on tumorigenesis by either antagonizing the cytotoxic activity of immune cells or, less frequently, by enhancing antitumor responses. In most situations, TAMs suppress T cell recruitment and function or regulate other aspects of tumor immunity. The importance of TAMs targeting in cancer therapy is derived from the strong association between the high infiltration of TAMs in the tumor tissue with poor patient prognosis. Several macrophage-targeting approaches in anticancer therapy are developed, including TAM depletion, inhibition of new TAM differentiation, or re-education of TAM activation for cancer cell phagocytosis. In this review, we will describe the role of TAMs in tumor development, including such aspects as protumorigenic inflammation, immune suppression, neoangiogenesis, and enhancement of tissue invasion and distant metastasis. Furthermore, we will discuss therapeutic approaches that aim to deplete TAMs or, on the contrary, re-educate TAMs for cancer cell phagocytosis and antitumor immunity.

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Section: Depletion Of Tams In the Tmementioning

confidence: 99%

The Role of Macrophages in Cancer Development and Therapy

Cendrowicz

Sas

Bremer

et al. 2021

Cancers

193

106

View full text Add to dashboard Cite

show abstract

“…Moreover, novel bi- and tri-valent T cell engagers activate endogenous T cells, and specifically deplete M2-like TAMs with retaining antitumor M1-like TAMs [ 62 ]. TD-92 is a new type of erlotinib derivative, which enhances the antitumor effect of anti-PD-1 and depletes TAMs by downregulating CSF-1R [ 63 ].…”

Section: Tam-targeting Therapymentioning

confidence: 99%

Targeting tumor-associated macrophages for cancer treatment

Zhu

et al. 2022

Cell Biosci

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Tumor-associated macrophages (TAMs) are abundant, nearly accounting for 30–50% of stromal cells in the tumor microenvironment. TAMs exhibit an immunosuppressive M2-like phenotype in advanced cancer, which plays a crucial role in tumor growth, invasion and migration, angiogenesis and immunosuppression. Consequently, the TAM-targeting therapies are particularly of significance in anti-cancer strategies. The application of TAMs as anti-cancer targets is expected to break through traditional tumor-associated therapies and achieves favorable clinical effect. However, the heterogeneity of TAMs makes the strategy of targeting TAMs variable and uncertain. Discovering the subset specificity of TAMs might be a future option for targeting TAMs therapy. Herein, the review focuses on highlighting the different modalities to modulate TAM’s functions, including promoting the phagocytosis of TAMs, TAMs depletion, blocking TAMs recruitment, TAMs reprogramming and suppressing immunosuppressive tumor microenvironment. We also discuss about several ways to improve the efficacy of TAM-targeting therapy from the perspective of combination therapy and specificity of TAMs subgroups.

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“…Erlotinib, a first-generation small-molecule inhibitor targeting the epidermal growth factor receptor (EGFR) tyrosine kinase, is suitable for the first-line treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). Combination therapy consisting of its derivative TD-92 and anti-PD-1 contributes to reduced tumor growth and increased survival in vivo ( 74 ).…”

Section: Modulation Of Tams To Elevate Anti-pd-1/pd-l1 Immunotherapymentioning

confidence: 99%

Tumor-Associated Macrophages Regulate PD-1/PD-L1 Immunosuppression

2022

Front. Immunol.

118

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Anti-programmed cell death 1 (PD-1) or anti-PD-ligand (L) 1 drugs, as classic immune checkpoint inhibitors, are considered promising treatment strategies for tumors. In clinical practice, some cancer patients experience drug resistance and disease progression in the process of anti-PD-1/PD-L1 immunotherapy. Tumor-associated macrophages (TAMs) play key roles in regulating PD-1/PD-L1 immunosuppression by inhibiting the recruitment and function of T cells through cytokines, superficial immune checkpoint ligands, and exosomes. There are several therapies available to recover the anticancer efficacy of PD-1/PD-L1 inhibitors by targeting TAMs, including the inhibition of TAM differentiation and re-education of TAM activation. In this review, we will summarize the roles and mechanisms of TAMs in PD-1/PD-L1 blocker resistance. Furthermore, we will discuss the therapies that were designed to deplete TAMs, re-educate TAMs, and intervene with chemokines secreted by TAMs and exosomes from M1 macrophages, providing more potential options to improve the efficacy of PD-1/PD-L1 inhibitors.

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TD-92, a novel erlotinib derivative, depletes tumor-associated macrophages in non-small cell lung cancer via down-regulation of CSF-1R and enhances the anti-tumor effects of anti-PD-1

Cited by 17 publications

References 51 publications

The Role of Macrophages in Cancer Development and Therapy

The Role of Macrophages in Cancer Development and Therapy

Targeting tumor-associated macrophages for cancer treatment

Tumor-Associated Macrophages Regulate PD-1/PD-L1 Immunosuppression

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