“Biopharmaceutical company Innate Pharma SA (euronext paris:FR0010331421) reported on Monday that it has started the cohort expansion portion of the Phase I clinical trial testing the combination of the two investigational checkpoint inhibitors lirilumab and nivolumab in selected solid tumors…
“The company said the trial will test lirilumab (anti-KIR checkpoint inhibitor; BMS-986015) in combination with nivolumab (anti-PD-1 checkpoint inhibitor BMS-936558) in solid tumors. The Phase I open label study will evaluate the safety of the combination of lirilumab and nivolumab and to provide preliminary information on the clinical activity of the combination. The primary outcome is safety.”
Editor’s note: Nivolumab is an immunotherapy drug that activates the immune system’s T cells in the hopes that the patient’s own immune system will be prompted to fight tumors. Nivolumab has already been shown to be a promising melanoma treatment on its own. Lirilumab is a drug that activates a different group of immune system cells known as natural killer cells (NK). This clinical trial combines both drugs to see if they work better together.
Liu G, Lu S, Wang X, Page ST, et al. J Clin Invest. Sep 9, 2013.
“The activating receptor NK cell group 2 member D (NKG2D) mediates antitumor immunity in experimental animal models. However, whether NKG2D ligands contribute to tumor suppression or progression clinically remains controversial. Here, we have described 2 novel lines of “humanized” bi-transgenic (bi-Tg) mice in which native human NKG2D ligand MHC class I polypeptide-related sequence B (MICB) or the engineered membrane-restricted MICB (MICB.A2) was expressed in the prostate of the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of spontaneous carcinogenesis. Bi-Tg TRAMP/MICB mice exhibited a markedly increased incidence of progressed carcinomas and metastasis, whereas TRAMP/MICB.A2 mice enjoyed long-term tumor-free survival conferred by sustained NKG2D-mediated antitumor immunity. Mechanistically, we found that cancer progression in TRAMP/MICB mice was associated with loss of the peripheral NK cell pool owing to high serum levels of tumor-derived soluble MICB (sMICB). Prostate cancer patients also displayed reduction of peripheral NK cells and high sMIC levels. Our study has not only provided direct evidence in “humanized” mouse models that soluble and membrane-restricted NKG2D ligands pose opposite impacts on cancer progression, but also uncovered a mechanism of sMIC-induced impairment of NK cell antitumor immunity. Our findings suggest that the impact of soluble NKG2D ligands should be considered in NK cell–based cancer immunotherapy and that our unique mouse models should be valuable for therapy optimization.”
Beavis PA, Divisekera U, Paget C, Chow MT, et al. Proc Natl Acad Sci U S A. Aug 20, 2013.
“CD73 inhibits antitumor immunity through the activation of adenosine receptors expressed on multiple immune subsets. CD73 also enhances tumor metastasis, although the nature of the immune subsets and adenosine receptor subtypes involved in this process are largely unknown. In this study, we revealed that A2A/A2B receptor antagonists were effective in reducing the metastasis of tumors expressing CD73 endogenously (4T1.2 breast tumors) and when CD73 was ectopically expressed (B16F10 melanoma). A2A-/- mice were strongly protected against tumor metastasis, indicating that host A2A receptors enhanced tumor metastasis. A2A blockade enhanced natural killer (NK) cell maturation and cytotoxic function in vitro, reduced metastasis in a perforin-dependent manner, and enhanced NK cell expression of granzyme B in vivo, strongly suggesting that the antimetastatic effect of A2A blockade was due to enhanced NK cell function. Interestingly, A2B blockade had no effect on NK cell cytotoxicity, indicating that an NK cell-independent mechanism also contributed to the increased metastasis of CD73+ tumors. Our results thus revealed that CD73 promotes tumor metastasis through multiple mechanisms, including suppression of NK cell function. Furthermore, our data strongly suggest that A2A or A2B antagonists may be useful for the treatment of metastatic disease. Overall, our study has potential therapeutic implications given that A2A/A2B receptor antagonists have already entered clinical trials in other therapeutic settings.”
Amaro A, Mirisola V, Angelini G, Musso A, et al. Eur J Cancer. Jul 9, 2013.
“Despite advances in surgery and radiotherapy of uveal melanoma (UM), many patients develop distant metastases that poorly respond to therapy. Improved therapies for the metastatic disease are therefore urgently needed. Expression of the epidermal growth factor receptor (EGFR), a target of kinase inhibitors and humanised antibodies in use for several cancers, had been reported. Forty-eight human UMs were analysed by expression profiling. Signalling was tested in three EGFR expressing UM cell lines by Western blotting using phosphorylation specific antibodies for EGFR and the downstream mediators AKT (v-akt murine thymoma viral oncogene homolog) and extracellular signal-regulated kinase (ERK). Evidence for signalling in tumours was obtained through the application of a UM-specific EGF-signature. The EGFR specific kinase inhibitor, Gefitinib and the humanised monoclonal antibody, Cetuximab, were tested for their effect on EGFR signalling. Natural killer cell mediated antibody-dependent cellular cytotoxicity (ADCC) and tumour necrosis factor α (TNF-α) release was analysed for Cetuximab.”
Bruno A, Focaccetti C ... Albini A, Noonan DM, Neoplasia, Feb 2013
The tumor microenvironment can polarize innate immune cells to a pro-angiogenic phenotype. Decidual NK cells show an angiogenic phenotype, yet the role for natural killer (NK) innate lymphoid cells in tumor angiogenesis remains to be defined. We investigated NK cells from patients with surgically resected non-small cell lung cancer (NSCLC) and controls. Our data suggest that NK cells in NSCLC act as pro-angiogenic cells, particularly evident for squamous cell carcinoma and in part mediated by TGFβ1.
Nambu A, Onishi H ... Sawada E, Araki T, BMC Cancer, Feb 7, 2013
As stereotactic body radiotherapy (SBRT) is a highly dose-dense radiotherapy, adverse events of neighboring normal tissues are a major concern. This study aimed to clarify the frequency and degree of clinical symptoms in patients with rib fractures after SBRT for primary lung cancer and to reveal risk factors for rib fracture. Appropriate alpha/beta ratios for discriminating between fracture and non-fracture groups were also investigated.
Rib fracture is frequently seen on CT after SBRT for lung cancer. Small tumor-chest wall distance and female sex are risk factors for rib fracture. However, clinical symptoms are infrequent and generally mild. When using BED analysis, an alpha/beta ratio of 8 Gy appears most effective for discriminating between fracture and non-fracture patients.