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1. Supplementary Figure 1. Illustration of tubes area detection as rectangles based on the bright field channel. 2. Supplementary Figure 2. Diarrhea severity during combination treatment with lumretuzumab (RO5479599), pertuzumab and paclitaxel in patients. 3. Full Unedited western blots of figures 2c and 2d

Combination of targeted therapies is expected to provide superior efficacy in the treatment of cancer either by enhanced antitumor activity or by preventing or delaying the development of resistance. Common challenges in developing combination therapies include the potential of additive and aggravated toxicities associated with pharmacologically related adverse effects. We have recently reported that combination of anti-HER2 and anti-HER3 antibodies, pertuzumab and lumretuzumab, along with paclitaxel chemotherapy in metastatic breast cancer, resulted in a high incidence of diarrhea that ultimately limited further clinical development of this combination. Here, we further dissected the diarrhea profile of the various patient dose cohorts and carried out in vitro investigations in human colon cell lines and explants to decipher the contribution and the mechanism of anti-HER2/3 therapeutic antibodies to intestinal epithelium malfunction. Our clinical investigations in patients revealed that while dose reduction of lumretuzumab, omission of pertuzumab loading dose, and introduction of a prophylactic antidiarrheal treatment reduced most severe adverse events, patients still suffered from persistent diarrhea during the treatment. Our in vitro investigations showed that pertuzumab and lumretuzumab combination treatment resulted in upregulation of chloride channel activity without indication of intestinal barrier disruption. Overall, our findings provide a mechanistic rationale to explore alternative of conventional antigut motility using medication targeting chloride channel activity to mitigate diarrhea of HER combination therapies. Mol Cancer Ther; 17(7); 1464–74. ©2018 AACR.

Cancer immunotherapy often involves the use of engineered molecules to selectively bind and activate T cells located within tumour tissue. Fundamental to the success of such treatments is the presence or recruitment of T cells localised within the tumour microenvironment. Advanced organ-on-a-chip systems provide an

The multiphasic etiology of tissue inflammation and the fundamental immunological differences between species render inflammatory pathologies difficult to recapitulate in animal models, and account for the paucity of therapies that are successfully translated from rodents to humans. Here, we present a human-relevant organ-on-a-chip platform for experimental inflammatory diseases. We created an immunocompetent in vitro gut model by incorporating intestinal epithelial and immune cells into microfluidic chambers that permit cell movement across an extracellular matrix (ECM) and fluidic channels. This is the first model that integrates a mucosal barrier, a three-dimensional ECM, resident and infiltrating immune cells, and simulates a functional crosstalk that ultimately triggers cellular processes representative of inflammation. Under homeostatic conditions, enterocytes form a tight epithelium and subepithelial macrophages are non-activated. Introduction of pro-inflammatory mediators triggers macrophage activation and inflammation-induced intestinal barrier leakiness. Neutrophils in a parallel, matrix-separated non-epithelial channel are attracted by such a pro-inflammatory microenvironment and migrate through the extracellular matrix, further exacerbating tissue inflammation and damage. With this model, we provide the foundations to recapitulate and investigate the onset of tissue inflammation in a controlled, human-relevant system.

Combination of targeted therapies is expected to provide superior efficacy in the treatment of cancer either by enhanced antitumor activity or by preventing or delaying the development of resistance. Common challenges in developing combination therapies include the potential of additive and aggravated toxicities associated with pharmacologically related adverse effects. We have recently reported that combination of anti-HER2 and anti-HER3 antibodies, pertuzumab and lumretuzumab, along with paclitaxel chemotherapy in metastatic breast cancer, resulted in a high incidence of diarrhea that ultimately limited further clinical development of this combination. Here, we further dissected the diarrhea profile of the various patient dose cohorts and carried out in vitro investigations in human colon cell lines and explants to decipher the contribution and the mechanism of anti-HER2/3 therapeutic antibodies to intestinal epithelium malfunction. Our clinical investigations in patients revealed that while dose reduction of lumretuzumab, omission of pertuzumab loading dose, and introduction of a prophylactic antidiarrheal treatment reduced most severe adverse events, patients still suffered from persistent diarrhea during the treatment. Our in vitro investigations showed that pertuzumab and lumretuzumab combination treatment resulted in upregulation of chloride channel activity without indication of intestinal barrier disruption. Overall, our findings provide a mechanistic rationale to explore alternative of conventional antigut motility using medication targeting chloride channel activity to mitigate diarrhea of HER combination therapies. Mol Cancer Ther; 17(7); 1464–74. ©2018 AACR.