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Effective treatment options are still scarce for metastatic triple-negative breast cancers. An increasing interest in the mutational landscape of this disease will facilitate novel therapeutic strategies in a variety of cancers. Here we report the case of a 38-year-old female patient who developed multiple lung metastasis of a triple-negative breast cancer 2 years after the completion of local therapy. When she progressed after two palliative chemotherapy lines and local electroporation, a next-generation sequencing revealed a BRAF V600E mutation for which we initiated therapy with the BRAF inhibitor vemurafenib. Radiological improvement was already evident after 3 months and has been ongoing for 19 months so far with very few side effects, as is demonstrated by electronically captured patient-reported outcomes. To our knowledge, this is the first published case where a BRAF V600E-mutated advanced triple-negative breast cancer was successfully treated with vemurafenib.

The success of cancer immunotherapy is limited by potent endogenous immune‐evasion mechanisms, which are at least in part mediated by transforming growth factor‐β (TGF‐β). The E3 ubiquitin ligase Cbl‐b is a key regulator of T cell activation and is established to regulate TGF‐β sensitivity. cblb‐deficient animals reject tumors via CD8+ T cells, which make Cbl‐b an ideal target for improvement of adoptive T‐cell transfer (ATC) therapy. In this study, we show that cblb‐deficient CD8+ T cells are hyper‐responsive to T‐cell receptor (TCR)/CD28‐stimulation and are in part protected against the negative cues induced by TGF‐β in vitro. Notably, adoptive transfer of polyclonal, non‐TCR transgenic cblb‐deficient CD8+ T cells is not sufficient to reject B16‐ova or EG7 tumors in vivo. Thus, cblb‐deficient ATC requires proper in vivo re‐activation by a dendritic cell (DC) vaccine. In strict contrast to ATC monotherapy, this approach delayed tumor outgrowth and significantly increased survival rates, which is paralleled by increased CD8+ T‐cells infiltration to the tumor site and enrichment of ova‐specific and interferon‐γ (IFN‐γ)‐secreting CD8+ T cell in the draining lymph node (LN). Moreover, CD8+ T cells from cblb‐deficient mice vaccinated with the DC vaccine show increased cytolytic activity in vivo. In summary, our data using cblb‐deficient polyclonal, non‐TCR‐transgenic adoptively transferred CD8+ T cells into immuno‐competent non‐lymphodepleted recipients suggest that targeting Cbl‐b might serve as a novel ‘adjuvant approach’, suitable to augment the effectiveness of established anti‐cancer immunotherapies.

BackgroundMedian survival of advanced malignant pleural mesothelioma (MPM) is less than 2 years, and novel treatments are urgently needed. Immunotherapy with adoptive T cell transfer is an attractive approach that could be added to current therapeutic concepts. Fibroblast activation protein (FAP) is expressed by all subtypes of MPM [1] and can serve as target of re-directed T cells harboring an anti-FAP chimeric antigen receptor (CAR) leading to site-specific T cell activation.Patients and methodsThis is a Phase I study with the primary clinical endpoint of safety and the secondary endpoints of feasibility and immune monitoring. Immune monitoring includes measurement of T cell subpopulations, cytokines and inflammatory parameters. This is the first in human application of FAP-specific autologous re-directed T cells in patients with newly diagnosed, inoperable MPM in the malignant pleural effusion. We report here on the first patient treated in February 2015. At that time, he was 74 years old and had received the diagnosis of MPM in November 2014. After 2 cycles of standard chemotherapy (Cisplatin/Pemetrexed), 250 ml of peripheral blood were collected (day -21), CD 8 T cells extracted and retro-virally transduced with a FAP-specific CAR, while the patient was receiving the 3rd cycle of chemotherapy. On day 0 1x106 CAR T cells were injected under sterile conditions into the pleural effusion through a pleural drainage on the intensive care unit (ICU), followed by 48 hours ICU surveillance. Simultaneously, cytokine levels were measured in the serum and in the pleural effusion.ResultsIn this first patient, we demonstrated safety and technical feasibility of the application of re-directed T cells. No adverse events due to the injection were observed, in particular no immune-mediated toxicity (e.g. cytokine storm, inflammation). Ex vivo analysis showed antigen-specific activity and function of re-directed T cells.ConclusionRe-directed T cells against FAP could be a safe and feasible treatment option for patients with MPM in the future. Further studies are needed to demonstrate anti-tumor efficacy.

AimsTo quantify the change in drusen volume over time and identify its prognostic value for individual risk assessment.MethodsA prospective observational study over a minimum of 3 years and maximum of 5 years and follow-up examination every 3 months was conducted at the ophthalmology department of the Medical University of Vienna. 109 patients presenting early and intermediate age-related macular degeneration (AMD) were included, of which 30 patients concluded a regular follow-up for at least 3 years. 50 eyes of 30 patients were imaged every 3 months using spectral-domain and polarisation-sensitive optical coherence tomography (OCT). Drusen volume was measured using an automated algorithm. Data of a 6-month follow-up were segmented manually by expert graders.ResultsGradings from 24 000 individual B-scans showed solid correlation between manual and automated segmentation with an initial mean drusen volume of 0.17 mm3. The increase in drusen volume was shown to be comparable among all eyes, and a model for long-term drusen volume development could be fitted as a cubic polynomial function and an R2=0.955. Spontaneous drusen regression was observed in 22 of 50 eyes. In this group, four eyes developed choroidal neovascularisation and three geographic atrophy.ConclusionsDrusen volume increase over time can be described by a cubic function. Spontaneous regression appears to precede conversion to advanced AMD. OCT might be a promising tool for predicting the individual risk of progression of AMD.

Purpose: To assess retinal function in areas of presumed fibrosis due to neovascular age-related macular degeneration (nAMD), using multimodal imaging and structure-function correlation. Design: Cross-sectional observational study. Methods: 30 eyes of 30 consecutive patients with nAMD with a minimum history of one year of anti-vascular endothelial growth factor therapy were included. Each patient underwent microperimetry (MP), color fundus photography (CFP), standard spectral-domain-based OCT (SD-OCT), and polarization sensitive-OCT (PS-OCT) imaging. PS-OCT technology can depict retinal fibrosis based on its birefringence. CFP, SD-OCT, and PS-OCT were evaluated independently for the presence of fibrosis at the corresponding MP stimuli locations. MP results and morphologic findings in CFP, SD-OCT, and PS-OCT were co-registered and analyzed using mixed linear models. Results: In total, 1350 MP locations were evaluated to assess the functional impact of fibrosis according to a standardized protocol. The estimated means of retinal areas with signs of fibrosis were 12.60 db (95% confidence interval: 10.44–14.76) in CFP, 11.60 db (95% COI: 8.84–14.36) in OCT, and 11.02 db (95% COI 8.10–13.94) in PS-OCT. Areas evaluated as subretinal fibrosis in three (7.2 db) or two (10.1 db) modalities were significantly correlated with a lower retinal sensitivity than a subretinal fibrosis observed in only one (15.3 db) or none (23.3 db) modality (p < 0.001). Conclusions: CFP, SD-OCT and PS-OCT are all suited to detect areas of reduced retinal sensitivity related to fibrosis, however, a multimodal imaging approach provides higher accuracy in the identification of areas with low sensitivity in MP (i.e., impaired retinal function), and thereby improves the detection rate of subretinal fibrosis in nAMD.