Elevated baseline lactate dehydrogenase was linked to shorter PFS. SHR-1701 combined with XELOX and bevacizumab demonstrated a manageable safety profile and potent antitumor activity in unresectable mCRC.

An immune/metabolism score integrating the features of six genes was developed as a predictive biomarker for immunotherapy response in multiple cohorts, allowing for the selection of patients most likely to experience positive outcomes from this therapy regimen. In conclusion, our study provides proof-of-concept data supporting the potential of SHR-1701 plus famitinib as an effective and safe subsequent-line therapy for refractory BTC and PDAC, highlighting the promise of targeting PD-L1, TGF-β, and angiogenesis pathways simultaneously.

P2, N=20, Not yet recruiting, Fudan University

P1/2, N=25, Completed, Nanjing Leads Biolabs Co.,Ltd | Recruiting --> Completed | N=202 --> 25 | Trial completion date: Dec 2024 --> Dec 2023 | Trial primary completion date: Oct 2024 --> Dec 2023

P1, N=245, Recruiting, Incyte Corporation | N=165 --> 245

Activation of the TGFβ/Smad signaling pathway was found involved in AMIGO2-induced EMT, and treatment with the TGFβ receptor inhibitor LY2109761 suppressed AMIGO2-induced EMT...These results suggest that the nuclear translocation of AMIGO2 induces EMT to promote CRC invasion by activating the TGFβ/Smad signaling pathway. Thus, AMIGO2 is an attractive therapeutic target for inhibiting EMT and metastatic CRC progression.

P1, N=13, Terminated, Jiangsu HengRui Medicine Co., Ltd. | N=345 --> 13 | Recruiting --> Terminated; Sponsor R&D strategy adjustment

P2/3, N=81, Terminated, Suzhou Suncadia Biopharmaceuticals Co., Ltd. | N=896 --> 81 | Trial completion date: Dec 2027 --> Apr 2024 | Enrolling by invitation --> Terminated | Trial primary completion date: Jul 2027 --> Apr 2024; R&d strategy adjustment

P1/2, N=81, Completed, Suzhou Suncadia Biopharmaceuticals Co., Ltd. | Recruiting --> Completed | Trial completion date: Dec 2023 --> Mar 2024 | Trial primary completion date: Dec 2021 --> Mar 2024

The blocking effect of SHR-1701 on TGF-β1 was verified by inhibiting peritoneal metastases in xenografts. Collectively, the interplay of EGR1/TGF-β1/CD44s/STAT3 signaling between mesothelial cells and GC cells induces EMT and stemness phenotypes, offering potential as a therapeutic target for PM of GC.

P3, N=737, Active, not recruiting, Suzhou Suncadia Biopharmaceuticals Co., Ltd. | Recruiting --> Active, not recruiting

The TGF-β1 signaling was interfered by LY2109761, a TGF-β receptor 1 (TβR1) inhibitor, or TGF-β1 neutral antibody...IFT88 siRNA or KIF3a siRNA impaired PC formation resulted in an aggravated DNA damage in bystander cells, while elevated PC formation by CytoD or STIL siRNA resulted in a decrease of DNA damage. Furthermore, TGF-β1 induced more DNA damages in S phases cells which showed lower PC formation rate and less DNA damages in G /G phase cells which showed higher PC formation rate. This study demonstrates the particular role of primary cilia during RCM induced DNA damages through TGF-β1 signaling restriction and thereby provides a functional link between primary cilia and RIBEs.

P1, N=85, Active, not recruiting, BJ Bioscience, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Oct 2023 --> Oct 2024

Collectively, although TEXs lead to the initial activation of CAR T-cells, the effect of TEXs suppressed CAR T-cells, which can be rescued by LY2109761. A treatment regimen combining CAR T-cell therapy and TGF-β inhibitors might be a novel therapeutic strategy for refractory and relapsed B-cell lymphoma.

P1, N=19, Terminated, Suzhou Transcenta Therapeutics Co., Ltd. | N=55 --> 19 | Trial completion date: Dec 2023 --> Sep 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2023 --> Sep 2023; Corporate Decision

P1, N=165, Recruiting, Incyte Corporation | Not yet recruiting --> Recruiting | N=100 --> 165 | Trial completion date: May 2026 --> Dec 2026 | Trial primary completion date: May 2026 --> Dec 2026

P1, N=100, Not yet recruiting, Incyte Corporation

Totally, we initially identified the smoking-related epigenetic modifications in bladder cancer and constructed a corresponding prognostic model, which was also linked to disparate sensitivities to chemotherapeutics. Our findings would provide novel insights into the carcinogenesis, prognosis, and therapies in bladder cancer.

Additionally, in two independent PD-1 reporter assays, INCA33890 inhibited SHP recruitment and enhanced NFAT activation with a potency within an order of magnitude to that of pembrolizumab. Collectively, these results provide compelling data for an effective and specific approach to simultaneously antagonizing TGFβ and PD-1 signaling in tumors. Clinical development of INCA33890 in checkpoint inhibitor-resistant and other cancers has been initiated.

Notably, combined treatment with 5-FC further enhanced antitumor efficacy of engineered NK101 in the solid tumor model. Our results demonstrate successful generation of multigene-modified NK101 cell therapeutics exerting diverse mechanisms of antitumor action - activation receptor-mediated innate killing, antigen-specific killing, and bystander effect-mediated killing.

The induction of Tph-like cells by TGF-β3 mainly produced from tissue macrophages plays a pivotal role in the pathological processes of active LN by enhancing B cell differentiation in patients with SLE.

Irradiation can induce ESCC cells secreting DJ-1. Secreted DJ-1 enters bystander cells to initiate activation of the TGF-β1 pathway via the DJ-1/HSC70/Smad3 signaling axis. The TSP1/TGF-β1/Smad3 positive feedback pathway constitutes the core pathway that promotes ESCC metastasis. DJ-1 is a useful biomarker for predicting the efficacy of radiotherapy and a potential therapeutic target for reversing RIBE in ESCC. Schematic diagram showing the underlying mechanism that irradiation-induced secretion of DJ-1 accelerates the metastasis of bystander ESCC cells.

Implications: CAFs enhance CRC aggressiveness by reducing FLRT3 expression through activating TGF-β/SMAD4 signaling pathway. CAFs-targeted therapy and/or LY2109761 were promising treatments for CRC.

The levels of TβRII circulating extracellular vesicles (crEV) appears to correlate with tumor burden, metastasis and patient survival, thereby serve as a non-invasive screening tool to detect malignant breast tumor stages. Thus, our findings not only identify a possible mechanism by which breast cancer cells can promote T cell exhaustion and dampen host anti-tumor immunity, but may also identify a target for immune therapy against the most devastating breast tumors.

ALA-PDT suppresses the growth of oral precancerous cells by regulating the TGF-β signaling pathway, and its suppressive effect was enhanced using LY2109761. These results indicate that it could be a promising alternative treatment against oral precancerous lesions.

Use of LY2109761, a receptor inhibitor of TGF-βs/Smad signaling pathway, was associated with heat stress and COCl suppression of androgens' secretion and stimulated EMT in Leydig cells. These findings characterized a novel pathogenesis of cryptorchidism and provided a new idea for therapeutics.

WHSC1L1 overexpression could play potential roles in the progression of breast cancer, and targeting WHSC1L1 could be a potential strategy for the treatment of breast cancer.

Here we report TST005 anti-tumor activities in MC38 colorectal cancer and EMT-6 breast cancer models compared to M7824 (Merck’s PD-L1/TGF-βRII) analog and its safety profiles following single or repeated doses in rats and non-human primates (NHP). Based on the exposure of TST005 in monkeys and predicted exposure at First in Human (FIH) dose, the safety margin of TST005 will be higher than 200 and 500 folds calculated on Cmax and AUC respectively. In conclusion, we have demonstrated the antitumor activity of TST005 in PD/PD-L1 sensitive and resistant tumor models as well as the safety profile in NHP, TST005 has been granted for phase 1 clinical trials in USA (NCT04958434).

Objective: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell therapy using a genetically modified T-cell receptor (TCR) to improve recognition of cancer cells expressing NY-ESO-1/LAGE-1a...Exploratory endpoints include laboratory parameters, overall survival, and anti-GSK3901961 or -GSK3845097 titers as applicable... This study was funded by GSK (209012; NCT04526509). Editorial support was provided by Eithne Maguire, PhD and Katie Crossland, PhD of Fishawack Indicia, part of Fishawack Health, UK; funded by GSK. This abstract was previously presented at the American Association for Cancer Research (April 10–15 and May 17–21, 2021) and the American Society of Clinical Oncology Annual Meeting (June 4–8, 2021).

Taken together, we show that reprogramming events initiated by Oct4 and Sox2 induce a CD44 + /FOX3P - GSC cell subset with a T-reg-like immunosuppressive transcriptional profile via a TGFBR2-dependent mechanism. This research provides the first description of such neoplastic cells in any malignancy and has high potential translational impact since targeting these tumor cell subsets and their immunosuppressive mechanisms may be critical to the successful development of GBM immunotherapies.

Moreover, miR-488 was confirmed to be the most upregulated gene related to EphrinB2 releasing in fibroblasts after SCI and miR-488 initiates EphrinB2 expression and physical barrier building through MAPK signaling after SCI. Our study points toward elevated levels of active TGF-β as inducer and promoters of fibroblasts distribution, fibrotic scar formation, and EphrinB2 expression, and deletion of global TGF-β or the receptor of TGF-β in Col1α2 lineage fibroblasts significantly improve functional recovery after SCI, which suggest that TGF-β might be a therapeutic target in SCI.

In vitro experiments, bone marrow mesenchymal stem cells (BM-MSCs) acquired a CAFs phenotype after co-culture with leukemia cells, which produced high level of tumor-promoting growth factors and reduced the daunorubicin (DNR)-induced damage to B-ALL cells...Further LY2109761 and AMD3100 effectively decreased the activation of CAFs through inhibiting TGF-β receptor and CXCR4. Comparative experiments with MSCs and transformed CAFs prompted that CAFs had more obvious effect than MSCs on stimulating leukemia progression through accelerating leukemia cell migration and invasion. These results clarified the important role of CAFs in B-ALL progression and the possible mechanisms of CAFs activation in leukemia microenvironment, which might provide a theoretical basis for B-ALL patients to find more effective targeted therapies targeting the bone marrow microenvironment.

In conclusion, we have demonstrated that TST005 has enhanced immunomodulatory properties and can induce potent antitumor activity in preclinical tumor models that are not sensitive to PD-1/PD-L1 monotherapy. These results provide the rationale for further clinical evaluation of TST005 in patients with advanced solid tumors and less optimal response to first generation PD(L)-1 based immunotherapy.