Mologen (Germany)

Since 2023, the on-demand ridepooling service MOIA operates, as part of Hamburg's public transport, an integrated wheelchair-accessible service and offers subsidized fares for individuals with severe disabilities. This study analyzes one year of demand patterns in Hamburg following these enhancements, utilizing data analyses to assess their impact on service usage and accessibility. Findings reveal insights into distinct spatio-temporal user behavior, offering valuable guidance for the development of large-scale urban mobility solutions.

Understanding the mode and site of action of a herbicide is key for its efficient development, the evaluation of its toxicological risk, efficient weed control and resistance management. Recently, the mode of action (MoA) of the herbicide cinmethylin was identified in lipid biosynthesis with acyl-ACP thioesterase (FAT) as the site of action (SoA). Cinmethylin was registered for selective use in cereal crops for the control of grass weeds in 2020. Here, we present a high-resolution co-crystal structure of FAT in complex with cumyluron identified by a high throughput crystallization screen. We show binding to and inhibition of FAT by cumyluron. Furthermore, in an array of experiments consisting of FAT binding assays, FAT inhibition assays, physiological and metabolic profiling, we tested compounds that are structurally related to cumyluron and identified the commercial herbicides oxaziclomefone, methyldymron, tebutam and bromobutide, with so far unknown sites of action, as FAT inhibitors. Additionally, we show that the previously described FAT inhibitors cinmethylin and methiozolin bind to FAT in a nanomolar range, inhibit FAT enzymatic activity and lead to similar metabolic changes. Based on presented data, we corroborate cinmethylin and methiozolin as potent FAT inhibitors and identify FAT as the SoA of the herbicides cumyluron, oxaziclomefone, bromobutide, methyldymron and tebutam. © 2022 Society of Chemical Industry.

ABSTRACTActivation of Toll-like receptor 9 (TLR9) is known to foster innate and adaptive immune responses and thus improve immune-mediated control of malignant disease. Lefitolimod is a potent TLR9 agonist without chemical modification developed for immunotherapeutic strategies. Modulation of the tumor microenvironment (TME) is a crucial requirement for the response to various immunotherapies: Immunogenic (“hot”) tumors, characterized by their T cell-infiltrated TME, respond better compared to non-immunogenic (“cold”) tumors. It has been speculated that the mode-of-action of lefitolimod provides the necessary signals for activation of immune cells, their differentiation into anti-tumor effector cells and their recruitment into the TME. We investigated the effect of lefitolimod on TME, and its potency to induce synergistic anti-tumor effects when combined with immune checkpoint inhibitory antibodies (CPI) in a murine model. Indeed, we could show that treatment with single-agent lefitolimod beneficially modulated the TME, via infiltration of activated CD8+ cells and a shift in the macrophage population toward M1 phenotype. The result was a pronounced anti-tumor effect correlated with the magnitude of infiltrated immune cells and tumor-specific T cell responses. In line with this, lefitolimod led to persistent anti-tumor memory in the EMT-6 model after tumor re-challenge. This was accompanied by an increase of tumor-specific T cell responses and cross-reactivity against different tumor cells. Lefitolimod clearly augmented the limited anti-tumor effect of the CPI anti-PD1 in an A20 and anti-PD-L1 in a CT26 model. These properties of potent immune surveillance reactivation render lefitolimod an ideal candidate as therapeutic agent for immuno-oncology, e.g. improving CPI strategies.

687 Background: The use of TLR9 agonists for immunotherapeutic approaches is supported by preclinical and ongoing clinical studies. Lefitolimod, a covalently-closed dumbbell-shaped DNA construct, is an immune surveillance reactivator which broadly activates cells of the innate and adaptive immune system. The conversion of non-immunogenic (cold) tumors into immunogenic (hot) tumors, characterized by their T-cell infiltration, is a pre-requisite for response to immunotherapies. By its mode-of-action lefitolimod likely provides the necessary signals for activation of immune cells and their differentiation into anti-tumor effector cells as well as their recruitment to the tumor microenvironment (TME). Methods: To support the further clinical development of lefitolimod in mCRC, the syngeneic colon carcinoma model CT26 was used to evaluate anti-tumoral efficacy of lefitolimod and its modulation of the TME. The phenotype of T cells and macrophages present within tumor-infiltrating immune cells were analyzed by flow cytometry. Their localization within the tumor was investigated by immunohistochemistry. Results: Intratumoral injection of single-agent lefitolimod in the CT26 model resulted in reduced tumor growth. This was accompanied by an increased infiltration of T cells, in particular CD8+ T cells, into the tumor center. The CD8+ T cells were activated and showed an up-regulation of the cytolytic effector Granzyme B. Correspondingly, the ratio of activated CD8+ T cells with cytolytic function to regulatory T cells was increased by lefitolimod. Moreover, lefitolimod led to the recruitment of macrophages into the tumor and, importantly, an increase of M1 macrophages and a decrease of M2 macrophages inside the TME. Conclusions: Lefitolimod treatment resulted in modulation of the TME towards an increase of effector cells with anti-tumoral functions like cytotoxic CD8+ T cells and M1-type macrophages as well as a decrease of pro-tumoral M2-type macrophages. Therefore, lefitolimod provides the essential requirements for clinical response to immunotherapeutic drugs like checkpoint inhibitors. This predestines lefitolimod as combination partner in immuno-oncological trials.

3049 Background: The double-blind placebo-controlled phase 2 IMPACT trial aimed to assess the clinical efficacy, safety, and immunological effects of the potent TLR9 agonist MGN1703, given at the d...

Abstract Background. The first-in-man phase 1-2 clinical study (ASET study) of the cell-based therapeutic cancer vaccine MGN1601 included patients with advanced renal cell carcinoma (RCC) who failed previous therapies and had no further standard therapy available. MGN1601 consists of two active pharmaceutical ingredients in fixed combination: fourfold gene-modified allogeneic tumor cells expressing IL-7, GM-CSF, CD80 and CD154 through MIDGE® vectors and a TLR-9 agonist, the DNA-based immunomodulator dSLIM®. Methods. The ASET study is conducted as a multicentric, open, single-arm Phase 1-2 clinical trial. Clinical response (PD, SD, PR, CR) was evaluated using CT scans according to RECIST 1.1 criteria and immune related Response Criteria (irRC). The efficacy data were evaluated in terms of progression-free survival (PFS) and overall survival (OS) for the intended to treat (ITT) and the treated per protocol (TPP) populations of patients.Immune response was determined by the following parameters: ELISA of serum cytokines and chemokines, DTH to MGN1601, LTT assay to standard antigens, frequency and activation of plasmacytoid dendritic cells (pDC), myeloid dendritic cells (mDC), monocytes, natural killer cells (NK), NKT-, B-, and T cells. Blood mRNA and frequency of cytotoxic T cells by ELISPOT as well as tumor tissue were analyzed in a patient subgroup. Results. Nineteen patients, who had advanced stage RCC and failed up to 7 previous therapy lines (median 3 lines), were included. Nine of these patients completed the treatment phase per protocol (TPP), the others discontinued the study earlier due to PD. Currently, one patient is still in treatment phase. Median PFS in the TPP group was 12 weeks (3 months) and OS (not reached yet) 45 weeks (11 months). Three patients achieved disease control (one PR and two SD) after 12 weeks according to RECIST 1.1 criteria. Two patients are continuing treatment in the extension phase and are progression free since 37 and 46 weeks, respectively. Re-evaluation of tumor response data using irRC revealed one additional patient, who had a delayed tumor response 4 weeks after stop of treatment. Herewith, 4 out of 9 TPP patients (45%) achieved disease control. Of six patients receiving a targeted therapy following progress, four had substantial objective responses, suggesting that the study drug rendered their tumors more vulnerable to subsequent therapies. Immune analysis of the cell populations after 12 weeks showed trends towards increases of T cell, NKT-cell and pDC frequencies in those patients with clinical responses to the therapy, indicating anti-tumor immunity due to the study treatment. Conclusions. The therapeutic cancer vaccine MGN1601 shows promising efficacy in late stage mRCC patients. Results warrant further clinical studies with MGN1601. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-233. doi:1538-7445.AM2012-LB-233