Akio Osa

Interleukin-17A Promotes Lung Tumor Progression through Neutrophil Attraction to Tumor Sites and Mediating Resistance to PD-1 Blockade

Introduction Proinflammatory cytokine interleukin‐17A (IL‐17A) is overexpressed in a subset of patients with lung cancer. We hypothesized that IL‐17A promotes a protumorigenic inflammatory phenotype and inhibits antitumor immune responses. Methods We generated bitransgenic mice expressing a conditional IL‐17A allele along with conditional KrasG12D and performed immune phenotyping of mouse lungs, a survival analysis, and treatment studies with antibodies either blocking programmed cell death 1 (PD‐1) or IL‐6 or depleting neutrophils. To support the preclinical findings, we analyzed human gene expression data sets and immune profiled patient lung tumors. Results Tumors in IL‐17:KrasG12D mice grew more rapidly, resulting in a significantly shorter survival as compared with that of KrasG12D mice. IL‐6, granulocyte colony‐stimulating factor (G‐CSF), milk fat globule‐EGF factor 8 protein, and C‐X‐C motif chemokine ligand 1 were increased in the lungs of IL17:Kras mice. Time course analysis revealed that levels of tumor‐associated neutrophils were significantly increased, and lymphocyte recruitment was significantly reduced in IL17:KrasG12D mice as compared with in KrasG12D mice. In therapeutic studies PD‐1 blockade was not effective in treating IL‐17:KrasG12D tumors. In contrast, blocking IL‐6 or depleting neutrophils with an anti–Ly‐6G antibody in the IL17:KrasG12D tumors resulted in a clinical response associated with T‐cell activation. In tumors from patients with lung cancer with KRAS mutation we found a correlation between higher levels of IL‐17A and colony‐ stimulating factor 3 and a significant correlation among high neutrophil and lower T‐cell numbers. Conclusions Here we have shown that an increase in a single cytokine, IL‐17A, without additional mutations can promote lung cancer growth by promoting inflammation, which contributes to resistance to PD‐1 blockade and sensitizes tumors to cytokine and neutrophil depletion.

Relationship between progression-free survival and overall survival in patients with advanced non-small cell lung cancer treated with anticancer agents after first-line treatment failure.

The hazard ratio of progression‐free survival (PFS‐HR) generally does not reflect that of overall survival (OS‐HR) in advanced non‐small cell lung cancer (NSCLC) patients treated with first‐line therapy. Short survival post‐progression (SPP) better reflects the PFS‐HR and OS‐HR in simulations. We aimed to evaluate whether the PFS‐HR reflects the OS‐HR in NSCLC clinical trials for post‐first‐line treatments.

Tubular nephrotoxicity induced by docetaxel in non-small-cell lung cancer patients

Renal dysfunction is a characteristic of many patients with cancer; however, a standard therapy has not been established for stage III or IV non-small-cell lung cancer (NSCLC) complicated with chronic renal failure. Docetaxel has a proven significant activity against NSCLC. This agent is predominantly eliminated by hepatobiliary extraction and is safe in patients with renal failure, including dialysis patients. Docetaxel is, thus, a therapeutic option in that patient population. Here, we report acute tubular nephrotoxicity secondary to docetaxel in NSCLC patients, even in patients with normal renal function. Little is known about tubular nephrotoxicity induced by docetaxel; however, oncologists should be aware of its possibility.

A Rare Case of Pleomorphic Carcinoma of the Lung Harboring an Anaplastic Lymphoma Kinase (ALK) Rearrangement.

Molecular testing for anomalies, such as epidermal growth factor receptor mutations and anaplastic lymphoma kinase (ALK) rearrangement, is part of the current standard of care for non-small cell lung cancer, particularly adenocarcinoma. ALK rearrangement occurs most frequently in adenocarcinoma cells and rarely in non-adenocarcinoma cells. We herein report a rare case of pleomorphic lung carcinoma with ALK rearrangement in both its adenocarcinoma and spindle cell components. This case suggests the possibility of ALK rearrangement in pleomorphic carcinoma.

Nanoparticle Albumin-bound Paclitaxel+Carboplatin Therapy for Small Cell Lung Cancer Combined with Squamous Cell Carcinoma and Interstitial Lung Disease.

It has recently been shown that nanoparticle albumin-bound paclitaxel (nab-PAC)+carboplatin (CBDCA) provides a favorable overall response rate in non-small cell lung cancer. This is the first case report of nab-PAC+CBDCA therapy in small cell lung cancer (SCLC). Our patient was a 72-year-old man with stage IV SCLC combined with squamous cell carcinoma and interstitial lung disease (ILD). We administered nab-PAC+CBDCA as a second-line chemotherapy. A partial response was evident after two cycles of chemotherapy, and no serious side effects occurred. The progression-free survival was 15 weeks. Second-line chemotherapy using nab-PAC+CBDCA was effective and well tolerated in an SCLC patient with ILD.

Clinical implications of monitoring nivolumab immunokinetics in non–small cell lung cancer patients

BACKGROUND. The PD-1–blocking antibody nivolumab persists in patients several weeks after the last infusion. However, no study has systematically evaluated the maximum duration that the antibody persists on T cells or the association between this duration and residual therapeutic efficacy or potential adverse events. METHODS. To define the duration of binding and residual efficacy of nivolumab after discontinuation, we developed a simplified strategy for T cell monitoring and used it to analyze T cells from peripheral blood from 11 non–small cell lung cancer patients previously treated with nivolumab. To determine the suitability of our method for other applications, we compared transcriptome profiles between nivolumab-bound and nivolumab-unbound CD8 T cells. We also applied T cell monitoring in 2 nivolumab-treated patients who developed progressive lung tumors during long-term follow-up. RESULTS. Prolonged nivolumab binding was detected more than 20 weeks after the last infusion, regardless of the total number of nivolumab infusions (2–15 doses) or type of subsequent treatment, in 9 of the 11 cases in which long-term monitoring was possible. Ki-67 positivity, a proliferation marker, in T cells decreased in patients with progressive disease. Transcriptome profiling identified the signals regulating activation of nivolumab-bound T cells, which may contribute to nivolumab resistance. In 2 patients who restarted nivolumab, T cell proliferation markers exhibited the opposite trend and correlated with clinical response. CONCLUSIONS. Although only a few samples were analyzed, our strategy of monitoring both nivolumab binding and Ki-67 in T cells might help determine residual efficacy under various types of concurrent or subsequent treatment. TRIAL REGISTRATION. University Hospital Medical Information Network Clinical Trials Registry, UMIN000024623. FUNDING. This work was supported by Japan Society for the Promotion of Science KAKENHI (JP17K16045, JP18H05282, and JP15K09220), Japan Agency for Medical Research and Development (JP17cm0106310, JP18cm0106335 and JP18cm059042), and Core Research for Evolutional Science and Technology (JPMJCR16G2).