PD-1 Inhibitors In Lung Cancer Research Articles

Low-dose carboplatin reprograms tumor immune microenvironment through STING signaling pathway and synergizes with PD-1 inhibitors in lung cancer.

Although the combination of chemotherapy and immunotherapy is a hot topic in lung cancer, little is understood regarding the possible mechanisms behind their synergy. Moreover, safety is a major concern for clinicians while performing chemotherapy. Therefore, it is important to determine the appropriate dose and period of chemotherapy for combining it with immunotherapy, and investigate the underlying synergistic mechanism. Here, we showed that carboplatin can induce DNA damage and activate the canonical STING/TBK1/IRF3 pathway and non-canonical STING-NF-κB signaling complex. Further, low-dose carboplatin changed the "cold" tumor into a "hot" tumor via the signaling hub STING, augmenting CD8+ T-cell infiltration, increasing PD-L1 expression, and hence potentiating the anti-tumor effect of PD-1 inhibitors; importantly, there were no adverse effects. Furthermore, knocking down STING in tumor cells effectively reversed PD-L1 upregulation and STING pathway activation, and reduced the anti-tumor effect of low-dose carboplatin and carboplatin-PD-1 inhibitor combination. Our findings collectively reported a previously unexplored role of low-dose carboplatin targeting in the STING pathway and provided an economical, useful and safe option for improving the efficacy of PD-1 inhibitors in lung cancer.

Abstract IA18: Early but promising data: PD-1 inhibitors in non-small cell lung cancer.

Abstract Blockade of the programmed death (PD-1) checkpoint has emerged as a promising approach for immunotherapies in the treatment of non-small cell lung cancer (NSCLC). Immune checkpoints, such as PD-1, an inhibitory T-cell immunoreceptor, and the receptor's ligands, PD-L1 and PD-L2, assist in hindering autoimmunity and protecting peripheral tissues to minimize damage (1). However, in cancers, the interaction between PD-1 and its ligands also can result in the promotion of an immunosuppressive tumor microenvironment (1). Several agents targeting PD-1 are currently undergoing clinical development. Clinical trials of anti-PD-1 antibodies nivolumab (BMS-936558) and MK-3475 have produced encouraging results in non-small cell lung cancer patients with regards to objective response rates (ORR) and progression free survival (PFS) (2,3). In a pretreated advanced NSCLC population, nivolumab produced durable responses, particularly at 3 and 10 mg/kg doses (2). For 38 previously-treated NSCLC patients, MK-3475, administered at 10 mg/kg every three weeks, led to an ORR of 24 percent based on irRC (21 percent based on RECIST 1.1) (3). Median overall survival was 51 weeks with a PFS, which had not been reached at a time when the minimum PFS would be 62 weeks among the responders (3). ORR was 67% in patients with tumors having PD-L1 expression above a cutpoint versus 4% in those below the cutpoint (3). Based on the favorable response rates relative to historical controls, and the durability of responses in clinical trials, the development of PD-1 inhibitors in lung cancer is proceeding rapidly. Future trials utilizing anti PD-1 antibodies will explore further biomarkers, and combination with other therapies. Citation Format: Edward B. Garon, Brian R. Wolf, Deborah JL Wong, Jonathan W. Goldman. Early but promising data: PD-1 inhibitors in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr IA18.