Liposome-induced immunosuppression and tumor growth is mediated by macrophages and mitigated by liposome-encapsulated alendronate.

Liposomal nanoparticles are the most commonly used drug nano-delivery platforms. However, recent reports show that certain pegylated liposomal nanoparticles (PLNs) and polymeric nanoparticles have the potential to enhance tumor growth and inhibit antitumor immunity in murine cancer models. We sought herein to identify the mechanisms and determine whether PLN-associated immunosuppression and tumor growth can be reversed using alendronate, an immune modulatory drug. By conducting in vivo and ex vivo experiments with the immunocompetent TC-1 murine tumor model, we found that macrophages were the primary cells that internalized PLN in the tumor microenvironment and that PLN-induced tumor growth was dependent on macrophages. Treatment with PLN increased immunosuppression as evidenced by increased expression of arginase-1 in CD11b+Gr1+ cells, diminished M1 functionality in macrophages, and globally suppressed T-cell cytokine production. Encapsulating alendronate in PLN reversed these effects on myeloid cells and shifted the profile of multi-cytokine producing T-cells towards an IFNγ+ perforin+ response, suggesting increased cytotoxic functionality. Importantly, we also found that PLN-encapsulated alendronate (PLN-alen), but not free alendronate, abrogated PLN-induced tumor growth and increased progression-free survival. In summary, we have identified a novel mechanism of PLN-induced tumor growth through macrophage polarization and immunosuppression that can be targeted and inactivated to improve the anticancer efficacy of PLN-delivered drugs. Importantly, we also determined that PLN-alen not only reversed protumoral effects of the PLN carrier, but also had moderate antitumor activity. Our findings strongly support the inclusion of immune-responsive tumor models and in-depth immune functional studies in the preclinical drug development paradigm for cancer nanomedicines, and the further development of chemo-immunotherapy strategies to co-deliver alendronate and chemotherapy for the treatment of cancer.

Update on targeted therapies for advanced non-small cell lung cancer: nivolumab in context.

While the initial treatment of non-small cell lung cancer (NSCLC) usually relies on surgical resection followed by systemic cytotoxic chemotherapy and/or radiation therapy, recent advances in understanding of NSCLC biology and immunology have spurred the development of numerous targeted therapies. In particular, a class of immune modulatory drugs targeting the immune checkpoint pathways has demonstrated remarkable durable remissions in a select minority of advanced NSCLC patients, potentially heralding the elusive "cancer cure". This review focuses on the clinical evidence for one of these agents, nivolumab, and clarifies the role of this drug in the context of the other targeted therapies currently available for the treatment of NSCLC. We also discuss the impact of nivolumab on patient quality of life and health economics.

Comparison of FT4 with log TSH on the Abbott Architect ci8200: Pediatric reference intervals for free thyroxine and thyroid-stimulating hormone.

BACKGROUND: We evaluated the clinical validity of serum FT4 measurements by assessing its correlation with log TSH. To provide pediatric reference intervals (representative ranges) for FT4, and TSH on the Architect ci8200 integrated system. METHODS: This population-based study encompassed 6023 children (3369 females and 2654 males). The percentile and Hoffmann approaches for obtaining reference intervals on these analytes were also compared. RESULTS: FT4 correlation with log TSH was poor ( r=0.010 for males and 0.050 for females). Reference intervals were established. TSH and FT4 did not show a significant sex difference; moreover, the intervals decreased with age for FT4 and TSH. CONCLUSIONS: Whereas in a previous study ultrafiltration tandem mass spectrometry yielded a correlation of r=0.90 for FT4 vs. log TSH this present study reveals a poor FT4 vs. log TSH correlation in the pediatric population studied and indicates the FT4 immunoassay conducted on the Abbott Architect ci8200 is less useful clinically than might have been expected. Reference intervals using the Hoffmann approach for pediatric in- and out-patients compare well with previously published results utilizing the percentile approach.