Recombinant Mutated Human TNF in Combination with Chemotherapy for Stage IIIB/IV Non-Small Cell Lung Cancer: A Randomized, Phase III Study

Abstract

Tumor necrosis factor (TNF), an anti-angiogenic agent in cancer treatment, is limited to isolated limb perfusion due to systemic toxicities. We previously prepared a TNF mutant (rmhTNF) that significantly improved responses in lung cancer patients and exhibited a promising safety profile in phase I and II studies. To further investigate whether rmhTNF with standard chemotherapy provides a survival benefit, 529 patients with stage IIIB/IV non-small cell lung cancer (NSCLC) were randomly assigned to receive docetaxel plus carboplatin/cisplatin with rmhTNF (265) or chemotherapy alone (264). After four cycles of treatment, the median overall survival was 13.7 months in the chemotherapy plus rmhTNF group compared with 10.3 months in the chemotherapy group (hazard ratio (HR) 0.75, P = 0.001). The median progression-free survival in the chemotherapy plus rmhTNF group and the chemotherapy group was 8.6 and 4.5 months (HR 0.76, P = 0.001), respectively, with corresponding response rates of 38.5% and 27.7% (P = 0.008). Increased hyperpyrexia and pulmonary hemorrhage were associated with rmhTNF, but most effects were well tolerated. The results indicated that rmhTNF effectively potentiated chemotherapy in patients with advanced NSCLC and was comparable with bevacizumab, an angiogenesis inhibitor approved by the Food and Drug Administration (FDA) for NSCLC.

Fibrocytes boost tumor-supportive phenotypic switches in the lung cancer niche via the endothelin system

“…An in-depth analysis of the chemotactic mechanisms attracting circulating fibrocytes to the lung cancer microenvironment was not the major focus of the present study, although inflammatory cytokines such as IL-2, TNFα and CXCR4 are implicated in fibrocyte recruitment under different disease conditions 32 – 35 . This is consistent with preceding observations from our own and other groups that markedly increased levels of cytokines, including IL-2, TNFα and CXCR4, are detected in experimental and human lung cancer tissue 19 , 24 , 36 – 38 . van Deventer et al reported that fibrocytes predispose the lung to B16-F10 metastasis by recruiting Ly-6C (+) monocytes 16 .…”

CEST theranostics: label-free MR imaging of anticancer drugs

“…Our results suggest that our approach is capable of directly monitoring delivery of nanoparticulate chemotherapeutics. Moreover, as TNF-α is being investigated clinically for improving the drug delivery of chemotherapy [ 26 ], this approach may also be useful for assessing the tumor responses to the combination of nanomedicine and TNF-α or other vascular-targeting treatment.…”

NLRP3/Caspase-1 inflammasome activation is decreased in alveolar macrophages in patients with lung cancer

“…TNF-α is a pro-inflammatory cytokine that is cytotoxic for tumor cells. It has been demonstrated that increased TNF-α levels in NSCLC correlate with improved outcomes, while TNF mutants have been proposed as anticancer chemotherapeutic drugs [ 61 , 62 ]. This dichotomous result in terms of antitumor immunity profiling could suggest a deregulation of the innate immunity mechanisms early on in the inflammasome process.…”