Invasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype, but ILC-specific trials are lacking. Translational research revealed an immune-related ILC subset... Show moreInvasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype, but ILC-specific trials are lacking. Translational research revealed an immune-related ILC subset, and in mouse ILC models, synergy between immune checkpoint blockade and platinum was observed. In the phase II GELATO trial (NCT03147040), patients with metastatic ILC were treated with weekly carboplatin (area under the curve 1.5 mg ml–1 min–1) as immune induction for 12 weeks and atezolizumab (PD-L1 blockade; triweekly) from the third week until progression. Four of 23 evaluable patients had a partial response (17%), and 2 had stable disease, resulting in a clinical benefit rate of 26%. From these six patients, four had triple-negative ILC (TN-ILC). We observed higher CD8+ T cell infiltration, immune checkpoint expression and exhausted T cells after treatment. With this GELATO trial, we show that ILC-specific clinical trials are feasible and demonstrate promising antitumor activity of atezolizumab with carboplatin, particularly for TN-ILC, and provide insights for the design of highly needed ILC-specific trials. Show less
The aim of this thesis was to gain further insight into the role of glucagon in glucose homeostasis in healthy volunteers and type 2 diabetes mellitus (T2DM) patients, and to explore the novel... Show moreThe aim of this thesis was to gain further insight into the role of glucagon in glucose homeostasis in healthy volunteers and type 2 diabetes mellitus (T2DM) patients, and to explore the novel antisense glucagon receptor antagonist. Chapter 2 showed that the effect of meal replacers containing protein hydrolysate on plasma glucose lowering is limited in T2DM patients due to a collective increase of both insulin and glucagon levels. In chapter 3 and 4 a glucagon challenge test in healthy volunteers and T2DM was studied and showed a good reproducibility and no confounding changes in autonomic nervous system tone. T2DM patients respond profoundly different to a glucagon challenge test compared to healthy volunteers and the response to a glucagon challenge test in T2DM subjects is influenced by the type of therapy. Chapter 5 provided the first proof of pharmacology of a novel antisense glucagon receptor antagonist in humans, ISIS 325568, as reflected by a reduction in glucagon-induced glucose excursion by using a well-characterized glucagon challenge test. In chapter 6 we designed a semi-mechanistic model which simultaneously describes glucagon, plasma glucose, insulin and glucagon receptor internalization using data from glucagon challenges in healthy volunteers. Show less
Dongen, M.G.J. van; Geerts, B.F.; Bhanot, S.; Morgan, E.S.; Kam, M.L. de; Moerland, M.; ... ; Burggraaf, J. 2014
