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ALK fusions were first described by Morris et al1 in 1994. Several studies have reported genetic alterations of the ALK gene in various tumor types since then, consisting of mutations, amplifications, and fusions.1-3 Fusion proteins have an active C-terminal tyrosine kinase domain in common.3 Here, we describe an STRN-ALK fusion in malignant peritoneal mesothelioma (MPM), which has previously been documented in other neoplasms, including thyroid cancer, renal carcinoma, leukemia, lymphoma, colon adenocarcinoma, head and neck adenocarcinoma, pericardial and peritoneal mesothelioma, and cutaneous squamous cell carcinoma.4-6 MPM is a rare disease with an incidence of approximately seven per million people per year.7 Patients' life expectancy is low (on average 12 months) because of the late clinical presentation with abdominal or pelvic pain or lymphadenopathy.8,9 Recently, ALK rearrangements have gained attention, especially in young female patients with MPM. Hung et al10 identified three ALK fusions in 88 consecutively screened patients with MPM. Fusion partners were ATG16L1, TPM1, and STRN. In another study by Mian et al,11 among 32 patients ��� 40 years old with mesothelioma (of which 25 were MPM), an ALK rearrangement was detected by fluorescence in situ hybridization in two patients (6%). One of the cases harbored an STRN-ALK fusion as described in the current case. Argani et al12 described additional five cases of ALK fusions in pediatric MPM. Subsequently, three more cases of STRN-ALK rearrangements in MPM have been published individually.6,13,14 In non���small-cell lung cancer (NSCLC), the discovery of specific drugs targeting ALK rearrangements led to significant therapeutic advances. Currently, various ALK inhibitors, namely, ceritinib, crizotinib, and alectinib, are used as first-line treatment in adult ALK-positive advanced NSCLC. Although crizotinib as a first-generation ALK inhibitor has already proven superiority over chemotherapy,15 next-generation ALK inhibitors such as ceritinib yielded even better survival rates.16 Moreover, both brigatinib and alectinib demonstrated superior effectiveness when directly compared with crizotinib.17,18 Unfortunately, resistance is frequently observed following an initial response in all these agents.19 Mechanisms of resistance, which often include ALK mutations, are in general universal although variable mutational frequencies are observed depending on the inhibitor.20 Despite this large base of knowledge for lung cancer, the evaluation of ALK fusions in other entities remains challenging because of limited available data.

Simple Summary In Molecular Tumor Boards (MTBs), clinicians and researchers discuss the biology of tumor samples from individual patients to find suitable therapies. MTBs have therefore become key elements of precision oncology programs. Patients living in urban areas with specialized medical centers can easily access MTBs. Dedicated efforts are necessary to also grant equal access for patients from rural areas. To address this challenge, the four German cancer centers in Würzburg, Erlangen, Regensburg and Augsburg collectively measured the regional efficacy of their MTBs. By jointly analyzing the residences of all MTB patients, we uncovered regional differences in our mostly rural catchment area. Mapping and further understanding these local differences—especially the underrepresented white spots—will help resolving inequalities in patient access to precision oncology. Our study represents a hands-on approach to assessing the regional efficacy of a precision oncology program. Moreover, this approach is transferable to other regions and clinical applications. Abstract (1) Background: molecular tumor boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs; (2) Methods: we analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities; (3) Results: the highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed for identifying so-called white spots—regions within our catchment that were relatively underrepresented in WERA MTBs; (4) Conclusions: investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in providing precision oncology and help establishing a joint WERA-wide outreach strategy.

Langerhans cell histiocytosis (LCH) is rare hematological neoplasia originating from the aberrant proliferation of CD207-positive dendritic cells. Refractory multi-system LCH is difficult to treat necessitating the continuous development of different salvage therapies. At our medical center, eleven patients (age 11 months to 77 years) with multi-system LCH were treated on a compassionate use basis with metronomic biomodulation therapy (MBT) involving the daily oral application of low-dose trofosfamide, etoricoxib, pioglitazone and low-dose dexamethasone. Overall, four patients including two heavily pretreated pediatric patients achieved ongoing complete remission. Moreover, partial disease remission was observed in three patients, and four patients attained stable disease. MBT demonstrated high activity against multi-system LCH even in patients, refractory to multiple systemic chemotherapies. Further confirmation of efficacy should be systematically evaluated in prospective trials.

BackgroundMolecular Tumor Boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs.MethodsWe analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities.ResultsHighest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed us to identify regions within our catchment area relatively underrepresented in WERA MTBs.ConclusionInvestigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in precision oncology and establishing a joint WERA-wide outreach strategy.

Molecular single cell analyses provide insights into physiological and pathological processes. Here, in a stepwise approach, we first evaluate 19 protocols for single cell small RNA sequencing on MCF7 cells spiked with 1 pg of 1,006 miRNAs. Second, we analyze MCF7 single cell equivalents of the eight best protocols. Third, we sequence single cells from eight different cell lines and 67 circulating tumor cells (CTCs) from seven SCLC patients. Altogether, we analyze 244 different samples. We observe high reproducibility within protocols and reads covered a broad spectrum of RNAs. For the 67 CTCs, we detect a median of 68 miRNAs, with 10 miRNAs being expressed in 90% of tested cells. Enrichment analysis suggested the lung as the most likely organ of origin and enrichment of cancer-related categories. Even the identification of non-annotated candidate miRNAs was feasible, underlining the potential of single cell small RNA sequencing., Technologies for small non-coding RNA sequencing at the single-cell level are less mature than for sequencing mRNAs. Here the authors evaluate available protocols for analysis of circulating lung cancer tumour cells.

Background: BNT211 comprises two drug products, a chimeric antigen receptor (CAR)-T cell product candidate that targets the tumor specific antigen claudin 6 (CLDN6) and a CAR-T cell-Amplifying RNA Vaccine (CARVac). In mice, CARVac mediates expansion of adoptively transferred CAR-T cells, improving their persistence and functionality. BNT211 aims to establish CAR-T cell therapy for CLDN6-positive solid tumors. Methods: This first-in-human, open label, multi-center trial involves a bifurcated 3+3 design with CLDN6 CAR-T cell dose escalations for both monotherapy (Part 1) and combination with CARVac (Part 2) following lymphodepletion. In Part 2, CARVac is applied q2/3w up to 100 days post CAR-T cell transfer, including a one-step intra-patient dose escalation followed by q6w maintenance dosing. Patients with CLDN6-positive relapsed or refractory solid tumors without further standard treatment options and ECOG 0-1 are eligible for recruitment. Results: As of 19th Jan 2022, 16 patients have been treated, with CAR-T cell transfer performed at dose levels (DLs) 1 and 2 for parts 1 and 2. In total, 37 ≥G3 AEs related to the drug product (mainly cytopenia, or transaminase and lipase elevations without clinical correlates) and 2 DLTs (G4 cytopenia at DL2, part 1 and G4 hemophagocytic lymphohistiocytosis at DL2, part 2) were reported (all resolved). Pronounced cytopenia occurred in patients with testicular cancer who had recently received high-dose chemotherapy and autologous stem cell transplantation. For these patients a lymphodepletion-free/reduced cohort was recently opened. Analysis of CAR-T cell frequency in peripheral blood revealed robust engraftment in all patients, with peak engraftment around day 17. Manageable cytokine release syndrome (G1-2) without any signs of neurotoxicity was observed in 8 patients. Administration of CARVac resulted in transient flu-like symptoms resolving within 24 h. Preliminary efficacy data of 12 evaluable patients 6 weeks after infusion showed 5 patients with PRs (with 39-49% shrinkage of target lesions), 6 with SD and 1 patient with PD (ORR 42%; DCR 92%), with responses seen in testicular and ovarian cancer patients. At 12 weeks, 5 of the 6 patients with PRs showed deepening of responses (50-73% shrinkage). In addition, one testicular cancer patient was treated with a 50% lymphodepletion regime and showed PR after 6 weeks. Conclusions: CLDN6 CAR-T cells ± CARVac show an acceptable safety profile at doses tested and encouraging signs of clinical activity. Data from the completed dose escalation phase will be presented. Acknowledgements: BNT211-01 is funded by BioNTech Cell & Gene Therapies GmbH. Trial registration: Clinicaltrials.gov: NCT04503278. Ethics approval: Ethics & Institutional Review Board approvals were obtained from the respective participating countries prior to initiation of the trial. Citation Format: John BAG Haanen, Andreas Mackensen, Christian Koenecke, Winfried Alsdorf, Eva Wagner-Drouet, Daniel Heudobler, Peter Borchmann, Carsten Bokemeyer, Sebastian Klobuch, Alexander Desuki, Florian Lüke, Erol Wiegert, Catrine Schulz, Benjamin Rengstl, Liane Preussner, Özlem Türeci, Ugur Sahin. BNT211: A Phase I trial to evaluate safety and efficacy of CLDN6 CAR-T cells and CARVac-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT002.

Metabolic pathways regulate immune responses and disrupted metabolism leads to immune dysfunction and disease. Coronavirus disease 2019 (COVID-19) is driven by imbalanced immune responses, yet the role of immunometabolism in COVID-19 pathogenesis remains unclear. By investigating 87 patients with confirmed SARS-CoV-2 infection, 6 critically ill non���COVID-19 patients, and 47 uninfected controls, we found an immunometabolic dysregulation in patients with progressed COVID-19. Specifically, T cells, monocytes, and granulocytes exhibited increased mitochondrial mass, yet only T cells accumulated intracellular reactive oxygen species (ROS), were metabolically quiescent, and showed a disrupted mitochondrial architecture. During recovery, T cell ROS decreased to match the uninfected controls. Transcriptionally, T cells from severe/critical COVID-19 patients showed an induction of ROS-responsive genes as well as genes related to mitochondrial function and the basigin network. Basigin (CD147) ligands cyclophilin A and the SARS-CoV-2 spike protein triggered ROS production in T cells in vitro. In line with this, only PCR-positive patients showed increased ROS levels. Dexamethasone treatment resulted in a downregulation of ROS in vitro and T cells from dexamethasone-treated patients exhibited low ROS and basigin levels. This was reflected by changes in the transcriptional landscape. Our findings provide evidence of an immunometabolic dysregulation in COVID-19 that can be mitigated by dexamethasone treatment.

Background: Most non-small cell lung cancers occur in elderly and frequently comorbid patients. Therefore, it is necessary to evaluate the efficacy of biomodulatory active therapy regimen, concertedly interfering with tumor-associated homeostatic pathways to achieve tumor control paralleled by modest toxicity profiles. Patients and Methods: The ModuLung trial is a national, multicentre, prospective, open-label, randomized phase II trial in patients with histologically confirmed stage IIIB/IV squamous (n = 11) and non-squamous non-small cell (n = 26) lung cancer who failed first-line platinum-based chemotherapy. Patients were randomly assigned on a 1:1 ratio to the biomodulatory or control group, treated with nivolumab. Patients randomized to the biomodulatory group received an all-oral therapy consisting of treosulfan 250 mg twice daily, pioglitazone 45 mg once daily, clarithromycin 250 mg twice daily, until disease progression or unacceptable toxicity. Results: The study had to be closed pre-maturely due to approval of immune checkpoint inhibitors (ICi) in first-line treatment. Thirty-seven patients, available for analysis, were treated in second to forth-line. Progression-free survival (PFS) was significantly inferior for biomodulation (N = 20) vs. nivolumab (N = 17) with a median PFS (95% confidence interval) of 1.4 (1.2–2.0) months vs. 1.6 (1.4–6.2), respectively; with a hazard ratio (95% confidence interval) of 1.908 [0.962; 3.788]; p = 0.0483. Objective response rate was 11.8% with nivolumab vs. 5% with biomodulation, median follow-up 8.25 months. The frequency of grade 3–5 treatment related adverse events was 29% with nivolumab and 10% with biomodulation. Overall survival (OS), the secondary endpoint, was comparable in both treatment arms; biomodulation with a median OS (95% confidence interval) of 9.4 (6.0–33.0) months vs. nivolumab 6.9 (4.6–24.0), respectively; hazard ratio (95% confidence interval) of 0.733 [0.334; 1.610]; p = 0.4368. Seventy-five percent of patients in the biomodulation arm received rescue therapy with checkpoint inhibitors. Conclusions: This trial shows that the biomodulatory therapy was inferior to nivolumab on PFS. However, the fact that OS was similar between groups gives rise to the hypothesis that the well-tolerable biomodulatory therapy may prime tumor tissues for efficacious checkpoint inhibitor therapy, even in very advanced treatment lines where poor response to ICi might be expected with increasing line of therapy.

Brain and leptomeningeal metastasis (LMM) of non-small cell lung cancer is still associated with poor prognosis. Moreover, the current diagnostic standard for LMM often yields false negative results and the scientific progress in this field is still unsatisfying. We present a case of a 71-year old patient with an isolated LMM. While standard diagnostics could only diagnose a cancer of unknown primary, the use of [68Ga]-Pentixafor-PET/CT (CXCR4-PET/CT, a radiotracer targeting CXCR4) and a liquid biopsy of the cerebrospinal fluid revealed the primary NSCLC. The detection of L858R-EGFR, a common driver mutation in NSCLC, enabled us to treat the patient with Afatinib and monitor treatment using [68Ga]-Pentixafor PET/CT. To estimate the impact of CXCR4 signaling and its ligands in NSCLC brain metastasis we looked at their expression and correlation with EGFR mutations in a primary and brain metastasis data set and investigated the previously described binding of extracellular ubiquitin to CXCR4. In conclusion, we describe a novel approach to improve diagnostics towards LMM and underline the impact of the CXCL12/CXCR4 axis in brain metastasis in a subset of NSCLC patients. We cannot confirm a correlation of CXCR4 expression with EGFR mutations or the binding of extracellular ubiquitin as previously reported.

Background The ModuLung trial addresses the medical need for low-toxic therapies in frequently comorbid patients with relapsed or refractory non-small cell lung cancer (NSCLC). We evaluated safety and efficacy of a biomodulatory approach in > =2nd-line, aiming for induction of anakoinosis i.e. communicative reprogramming of dysregulated cellular and intercellular homeostasis. Methods Patients with stage IIIB/IV squamous or non-squamous NSCLC and disease progression during or after at least one platinum-based chemotherapy were stratified according to histology, and randomly assigned 1:1 to treosulfan 250 mg twice daily, pioglitazone 45 mg once daily and clarithromycin 250 mg twice daily (experimental arm) or nivolumab 3 mg/kg every 2 weeks (control arm). The primary endpoint was progression-free survival (PFS). Results Due to the approval of checkpoint inhibitors in first-line, the study was prematurely closed after randomization of 40 of the 86 initially planned patients. The main efficacy and safety results are presented in the table and show no statistically significant difference between groups. The two-year survival rate achieved in the biomodulatory arm was 10% (95% CI, 1.2 to 31.7) and 5.9% (95% CI, 0.1 to 28.7) in the nivolumab arm. 75% and 53% of the patients proceeded to a further line of therapy, respectively. Table . 1570P Results Biomodulatory Arm (n = 20) 35% > 2nd-line Nivolumab Arm (n = 17) 41.2% > 2nd-line HR & 95% CI or p-value PFS, median in months 1.6 2.1 HR = 1.17; 95% CI, 0.59--2.34 OS, median in months 8.2 6.9 HR = 0.86; 95% CI, 0.38-1.96 ORR, n (%) 2 (10%) 0 (0%) P = 0.49 Grade 3-5 AE, n (%) 2 (10%) 6 (35%) P = 0.11 Conclusions Combination of clarithromycin, pioglitazone and metronomic chemotherapy is active in the > =2nd line treatment of NSCLC and warrants further investigations. Nivolumab did not induce any tumor response and was relatively toxic in this population. Novel treatment approaches are urgently needed for patients who previously received platinum-based chemotherapy for advanced squamous and non-squamous NSCLC (Funded by Anticancer Fund, EudraCT number 2014-004095-31). Clinical trial identification EudraCT: 2014-004095-31, Start Date: 2015-07-13. Legal entity responsible for the study Freistaat Bayern respresented by University of Regensburg represented by Kaufmannischer Direktor. Funding Anticancer Fund, Brussels, Belgium. Disclosure All authors have declared no conflicts of interest.

// Laila Siam 1 , Annalen Bleckmann 2, 3 , Han-Ning Chaung 2 , Alexander Mohr 4 , Florian Klemm 2 , Alonso Barrantes-Freer 5 , Raquel Blazquez 2 , Hendrik A. Wolff 6 , Florian Luke 7 , Veit Rohde 1 , Christine Stadelmann 5 , Tobias Pukrop 2, 7 1 Department of Neurosurgery, University Medical Center, Gottingen, Germany 2 Department of Hematology and Medical Oncology, University Medical Center, Gottingen, Germany 3 Department of Medical Statistics, University Medical Center, Gottingen, Germany 4 Department of Neuroradiology, University Medical Center, Gottingen, Germany 5 Institute of Neuropathology, University Medical Center, Gottingen, Germany 6 Department of Radiotherapy and Radiation Oncology, University Medical Center, Gottingen, Germany 7 Department of Internal Medicine III, Hematology and Medical Oncology, University Hospital Regensburg, Regensburg, Germany Correspondence to: Tobias Pukrop, e-mail: tobias.pukrop@ukr.de Keywords: astrocytes, brain metastasis, glial-pseudo capsule, metastatic infiltration, organ-specific defense Received: April 11, 2015 Accepted: June 08, 2015 Published: June 17, 2015 ABSTRACT The current approach to brain metastases resection is macroscopic removal of metastasis until reaching the glial pseudo-capsule (gross total resection (GTR)). However, autopsy studies demonstrated infiltrating metastatic cells into the parenchyma at the metastasis/brain parenchyma (M/BP)-interface. Aims/Methods: To analyze the astrocyte reaction and metastatic infiltration pattern at the M/BP-interface with an organotypic brain slice coculture system. Secondly, to evaluate the significance of infiltrating metastatic tumor cells in a prospective biopsy study. Therefore, after GTR, biopsies were obtained from the brain parenchyma beyond the glial pseudo-capsule and analyzed histomorphologically. Results: The coculture revealed three types of cancer cell infiltration. Interestingly, the astrocyte reaction was significantly different in the coculture with a benign, neuroectodermal-derived cell line. In the prospective biopsy study 58/167 (34.7%) samples revealed infiltrating metastatic cells. Altogether, 25/39 patients (64.1%) had proven to exhibit infiltration in at least one biopsy specimen with significant impact on survival (OS) (3.4 HR; p = 0.009; 2-year OS was 6.6% versus 43.5%). Exceptionally, in the non-infiltrating cohort three patients were long-term survivors. Conclusions: Metastatic infiltration has a significant impact on prognosis. Secondly, the astrocyte reaction at the M/BP-interface is heterogeneous and supports our previous concept of the organ-specific defense against metastatic (organ-foreign) cells.

Brain and leptomeningeal metastasis (LMM) of non-small cell lung cancer is still associated with poor prognosis. Moreover, the current diagnostic standard for LMM often yields false negative results and the scientific progress in this field is still unsatisfying. We present a case of a 71-year old patient with an isolated LMM. While standard diagnostics could only diagnose a cancer of unknown primary, the use of [68Ga]-Pentixafor-PET/CT (CXCR4-PET/CT, a radiotracer targeting CXCR4) and a liquid biopsy of the cerebrospinal fluid revealed the primary NSCLC. The detection of L858R-EGFR, a common driver mutation in NSCLC, enabled us to treat the patient with Afatinib and monitor treatment using [68Ga]-Pentixafor PET/CT. To estimate the impact of CXCR4 signaling and its ligands in NSCLC brain metastasis we looked at their expression and correlation with EGFR mutations in a primary and brain metastasis data set and investigated the previously described binding of extracellular ubiquitin to CXCR4. In conclusion, we describe a novel approach to improve diagnostics towards LMM and underline the impact of the CXCL12/CXCR4 axis in brain metastasis in a subset of NSCLC patients. We cannot confirm a correlation of CXCR4 expression with EGFR mutations or the binding of extracellular ubiquitin as previously reported.

Introduction: Patients (pts) with acute myeloid leukemia (AML) who are refractory to intensive frontline treatment have a dismal outcome. In case of ineligibility for allogeneic stem cell transplantation (HSCT), the median survival of chemo-refractory AML is about 2 months and less than 5% of these pts are alive after 1-year (retrospective analysis from the AMLSG database). To date, there is no universally accepted standard approach for the treatment of chemo-refractory AML in older pts. Several retrospective studies have assessed the role of hypomethylating agents in this patient group, but complete remission (CR) rates were disappointingly low (≤10%) when compared to first line treatment. The presented study represents a novel approach focusing on hematopoietic tissue reprogramming (i.e. anakoinosis) (ClinicalTrials.gov Identifier: NCT02942758). Methods: The initial dose-finding phase I of the study evaluated the combination of azacitidine (AZA) 75 mg/d s.c. for 7 days, repeated every 28-days, pioglitazone 45 mg/d p.o. continuously from day 1 and all-trans retinoic acid (ATRA). A modified 3+3 design has been used to establish the maximum-tolerated dose of ATRA. Patients have been enrolled at an ATRA dose of 45 mg/m²/d from day 1 to day 28 and 15 mg/m²/d continuously thereafter if no dose limiting toxicity (DLT) occurred until start of next cycle on day 29. The safety DLTs were defined as toxicities attributable to ATRA, expected or unexpected, except if these are likely associated with another cause. Eligible patients had confirmed diagnosis of AML refractory to induction therapy and were not eligible for further intensive induction therapy or were not immediate candidates for allogeneic HSCT. The severity of adverse events was graded using the Common Terminology Criteria for Adverse Events (CTCAE) V. 4.03. The response to treatment was evaluated using standard criteria defined by the expert panel on behalf of the European LeukemiaNet and international working group (IWG) response. Results: Ten pts were enrolled in the safety-run-in phase I (one pt withdrew informed consent on day 9 of cycle 1). Among all treated pts, the median age was 67 years (range, 62-76 years), and the majority of pts (70%) had an ECOG PS of 1 (see table 1). Two pts had secondary AML; another two pts had therapy-related AML (t-AML). Eight pts had a complex karyotype. Concerning safety, hematological adverse events (AEs) were the most common toxicities observed. Because pts with baseline cytopenia were included (leukopenia n=8; 80%; thrombocytopenia n=9; 90%), occurrences of many hematological AEs began before study drug initiation and were attributed to underlying hematologic disease. Common 3°/4° AEs included neutropenia (50%), anemia (50%), thrombocytopenia (30%), and infections (40%). 50% of pts experienced a serious AE; one 5° AE (gastric hemorrhage) occurred. No DLTs were observed. Five pts discontinued the study, with progressive disease (PD) or relapse being the most common reason for discontinuation. Concerning efficacy, 3 pts (30%) achieved a CR and one pt a long-lasting stable disease (14 months). Morphologic review showed signs of differentiation of blasts in responding pts, which has already been shown in in-vitro analysis. In line with this observation, one pt demonstrated resolution of fungal pneumonia during the study. Conclusions: In summary, the low-intensity, biomodulatory regimen of low-dose AZA, pioglitazone, and ATRA demonstrated a tolerable safety profile and encouraging signals for efficacy in pts with AML refractory to standard induction chemotherapy warranting further investigation. S.T. and A.R. contributed equally to this abstract as senior co-authors. Disclosures Paschka: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Abbvie: Other: Travel expenses; Amgen: Other: Travel expenses; Otsuka: Membership on an entity's Board of Directors or advisory committees; BMS: Other: Travel expenses, Speakers Bureau; Astex: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Other: Travel expenses; Takeda: Other: Travel expenses; Sunesis: Membership on an entity's Board of Directors or advisory committees. Döhner:Celgene, Novartis, Sunesis: Honoraria, Research Funding; AROG, Bristol Myers Squibb, Pfizer: Research Funding; AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria. Thomas:Celgene: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Medigene AG: Consultancy, Other: Travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Other: Travel support; Janssen: Other: Travel support.

8037 Background: Nowadays, therapy for relapsed or refractory multiple myeloma (rrMM) usually consists of multi-targeted combination regimens for achieving complete remission. In this context, resistance resembles a therapeutic challenge that may be overcome by novel biomodulatory therapies communicatively reprogramming dysregulated cellular and intercellular homeostasis in neoplasia. Methods: The present, prospective phase II, one-arm, one-stage multi-center, open label trial, following phase I, focused on reprogramming myeloma and adjacent stroma cells in order to control rrMM beyond > 2nd-line treatment and following lenalidomide resistance in prior line. Adults with rrMM were eligible for receiving continuously, oral, daily dexamethasone 1mg, pioglitazone 45mg, low-dose treosulfan as metronomic chemotherapy ( 250mg bid) and lenalidomide 15mg, respectively, until disease progression. Results: Thirty-nine patients (mean time since diagnosis, 5.7 years; 66.7% with age > 60 years) had received a median of 5.5 (range 2 to 10) prior treatments. 89.5% of the patients were refractory to last therapy (all IMiD resistant), and 48.7% had received autologous stem-cell transplants. The overall response rate (CR, VGPR) was 17.9%. Eighteen patients (46.2%) had partial response or better; ten patients (25.6%) had stable disease. The disease control rate (DCR) was 71.8%. Time-to-progression was not significantly different between IMiD refractory patients and those relapsing following prior IMiD therapy or between high-risk versus non-high-risk cytogenetics. The median progression-free survival (PFS) and overall survival was 5.6 months (95% confidence interval [CI], 3.8 to 8.5) and 17.6 months (95% [CI], 14.9 to 39.2), respectively. The major AE (NCI-CTCAE grade) with grade ≥ 3 and relation to study drugs was hematologic toxicity (N = 31, 67.4%). Due to scheduled dose reductions, this was associated with only 7 (15.2%) grade ≥ 3 infections. Conclusions: The favorable safety profile, encouraging efficacy and equivalent median PFS between biomodulatory and modern targeted therapy in a historic comparison reveal a proof of concept of combined biomodulatory therapy in patients with heavily pretreated and IMiD-resistant rrMM, which should be further evaluated. Clinical trial information: NCT001010243.

Molluscs with various shell architectures evolved around 542–525 million years ago, as part of a larger phenomenon related to the diversification of metazoan phyla. Molluscs deposit minerals in a chitin matrix. The mollusc chitin is synthesized by transmembrane enzymes that contain several unique extracellular domains. Here we investigate the assembly mechanism of the chitin synthase Ar-CS1 via its extracellular domain ArCS1_E22. The corresponding transmembrane protein ArCS1_E22TM accumulates in membrane fractions of the expression host Dictyostelium discoideum. Soluble recombinant ArCS1_E22 proteins can be purified as monomers only at basic pH. According to confocal fluorescence microscopy experiments, immunolabeled ArCS1_E22 proteins adsorb preferably to aragonitic nacre platelets at pH 7.75. At pH 8.2 or pH 9.0 the fluorescence signal is less intense, indicating that protein–mineral interaction is reduced with increasing pH. Furthermore, ArCS1_E22 forms regular nanostructures on cationic substrates as revealed by atomic force microscopy (AFM) experiments on modified mica cleavage planes. These experiments suggest that the extracellular domain ArCS1_E22 is involved in regulating the multiple enzyme activities of Ar-CS1 such as chitin synthesis and myosin movements by interaction with mineral surfaces and eventually by protein assembly. The protein complexes could locally probe the status of mineralization according to pH unless ions and pCO2 are balanced with suitable buffer substances. Taking into account that the intact enzyme could act as a force sensor, the results presented here provide further evidence that shell formation is coordinated physiologically with precise adjustment of cellular activities to the structure, topography and stiffness at the mineralizing interface.