134 Background: TLR9 agonists have shown anti-tumor effects by modulating the innate and adaptive immune system. Ongoing clinical studies support the use of TLR9 agonists for immunotherapeutic approaches. The new family of TLR9 agonists,... more
134 Background: TLR9 agonists have shown anti-tumor effects by modulating the innate and adaptive immune system. Ongoing clinical studies support the use of TLR9 agonists for immunotherapeutic approaches. The new family of TLR9 agonists, EnanDIM, consists of linear single-stranded ODN synthesized using L-deoxyribonucleotides (natural enantiomers of D-deoxyribonucleotides) at their 3’-ends to prevent degradation. Therefore, EnanDIM does not own the off-target effects of PTO-modified CpG-ODN. Methods: EnanDIM with varying nucleotid sequences were compared for IFN-alpha response from human peripheral blood mononuclear cells and those molecules inducing the stronges response were selected. A maximum feasible dose (MFD) approach was employed to evaluate their acute toxicity and immunomodulatory properties. In addition, a combinatory approach with aPD-1 was evaluated in an syngeneic colon carcinoma CT26 mouse tumor model. Results: EnanDIM581 and EnanDIM532 were selected due to their prono...
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Although 40–50% of adults and 70–80 % of children with acute lymphoblastic leukemia (ALL) can be cured by poly chemo therapy, the prognosis of patients with Philadelphia chromosome positive (Ph+) ALL remains poor. Therefore, new relapse... more
Although 40–50% of adults and 70–80 % of children with acute lymphoblastic leukemia (ALL) can be cured by poly chemo therapy, the prognosis of patients with Philadelphia chromosome positive (Ph+) ALL remains poor. Therefore, new relapse prevention strategies are needed for patients with Ph+ ALL during remission. We have shown previously, that vaccination of mice with leukemia cell lines modified to express costimulatory molecules and cytokines induce a systemic immunity against the syngeneic BCR-ABLp185 expressing leukemia cell line BM185. However, the difficulties to culture and transfect human leukemia cells limit the clinical application of leukemia cell based vaccines. Thus, we evaluated the immunization of mice with DNA-based vaccines subsequently challenged by the cell line BM185. Combinations of minimalistic immunogenically defined gene expression (MIDGE) vectors encoding a BCR-ABLp185 fusion specific peptide, GM-CSF, IL12, IL27 or CD40L were used for in vivo transfection of ...
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In contrast to gene therapy of solid tumors, only a few preclinical studies exist about gene therapy of acute lymphoblastic leukemia. Previously, we showed that vaccination of mice with syngeneic BCR-ABLp185 expressing leukemia cell lines... more
In contrast to gene therapy of solid tumors, only a few preclinical studies exist about gene therapy of acute lymphoblastic leukemia. Previously, we showed that vaccination of mice with syngeneic BCR-ABLp185 expressing leukemia cell lines modified to express costimulatory molecules and cytokines induce a systemic immunity against wild type leukemia. However, the difficulties to culture and transfect human leukemia cells limit the clinical application of leukemia cell based vaccines. Thus, we evaluated the pre-immunization of mice with DNA based vaccines subsequently challenged by the cell line BM185. In order to avoid the limitations and serious side effects associated with viral vectors we used nonviral gene delivery methods. Minimalistic immunogenically defined gene expression (MIDGE) vectors encoding a BCR-ABLp185 fusion specific peptide or GM-CSF were used as DNA vaccine and double stem-loop immunomodulators (dSLIM), containing three CpG-motifs were used as immune adjuvant. We p...
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Cytosine-guanine (CpG) motifs containing oligonucleotides (ODN) are commonly used for immunomodulatory purpose in cancer therapy and for the treatment of allergic diseases since they resemble bacterial DNA and serve as “danger signals”.... more
Cytosine-guanine (CpG) motifs containing oligonucleotides (ODN) are commonly used for immunomodulatory purpose in cancer therapy and for the treatment of allergic diseases since they resemble bacterial DNA and serve as “danger signals”. These CpG-ODNs promote predominately a TH1-response with secretion of IL-12 and IFN-γ, In addition their broad potential includes activation of B-cell proliferation, monocyte stimulation and secretion of IgM and IL-6, and stimulation of plasmacytoid DC to produce IFN-α/-β and thus γδT-cells and NK-cells to express CD69 and secrete IFN-γ. Usually phosphorothioate (PS) modifications are to enhance the stability, but these are leading to several side-effects, like severe organ enlargements, morphological changes and immunosuppression in mice. We designed immunomodulatory molecules based on short covalently-closed dumbbell-like structures (dSLIM) to stabilize the DNA without the otherwise necessary PS-modification. To evaluate the anti-tumor effect of th...
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DESIGN This was an exploratory, single-arm clinical trial that tested the immune enhancement effects of 24-weeks of Toll-like receptor 9 (TLR9) agonist (MGN1703; Lefitolimod; 60 mg × 2 weekly) therapy. METHODS We enrolled HIV-1-infected... more
DESIGN This was an exploratory, single-arm clinical trial that tested the immune enhancement effects of 24-weeks of Toll-like receptor 9 (TLR9) agonist (MGN1703; Lefitolimod; 60 mg × 2 weekly) therapy. METHODS We enrolled HIV-1-infected individuals on suppressive combination antiretroviral therapy. Safety was assessed throughout the study. The primary outcome was reduction in total CD4 T-cell viral DNA levels. Secondary outcomes included safety, detailed immunological and virological analyses, and time to viral rebound (viral load > 5000 copies/ml) after randomization into an analytical treatment interruption (ATI). RESULTS A total of 12 individuals completed the treatment phase and nine completed the ATI. Adverse events were limited and consistent with previous reports for MGN1703. Although the dosing regimen led to potent T-cell activation and increased HIV-1-specific T-cell responses, there were no cohort-wide changes in persistent virus (total CD4 T cells viral DNA; P = 0.34). No difference in time to rebound was observed between the ATI arms (log rank P = 0.25). One of nine ATI participants, despite harboring a large replication-competent reservoir, controlled viremia for 150 days via both HIV-1-specific cellular and antibody-mediated immune responses. CONCLUSION A period of 24 weeks of MGN1703 treatment was safe and improved innate as well as HIV-1-specific adaptive immunity in HIV-1+ individuals. These findings support the incorporation of TLR9 agonism into combination HIV-1 cure strategies. TRIAL NAME AND REGISTRATION TLR9 Enhancement of antiviral immunity in chronic HIV-1 infection: a phase 1B/2A trial; ClinicalTrials.gov NCT02443935.
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e14015 Background: The synthetic DNA-based immunomodulator MGN1703 acts as TLR-9 agonist by activating the innate and adaptive immune system. MGN1703 has already shown a good safety profile and a b...
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Introduction TLR9 agonists are developed as anti-cancer therapies based on their broad activation of the innate and adaptive immune system. Single-stranded oligodeoxynucleotides (ODN) containing non-methylated CG-motifs activate TLR9.... more
Introduction TLR9 agonists are developed as anti-cancer therapies based on their broad activation of the innate and adaptive immune system. Single-stranded oligodeoxynucleotides (ODN) containing non-methylated CG-motifs activate TLR9. Previously, chemical modification was used to prevent their degradation by exonucleases. To avoid the off-target effects observed with chemical modifications, new TLR9 agonists containing only natural DNA were stabilized by structural components. The dSLIM® family of TLR9 agonists is protected from exonucleolytic degradation by its covalently-closed dumbbell-shaped structure. It contains an immunomodulatory sequence with CG-motifs in its loops. The linear single-stranded EnanDIM® family of TLR9 agonists utilizes L-deoxyribonucleotides (natural enantiomers of D-deoxyribonucleotides) at their 3’-ends to prevent degradation. Since the mode-of-action of TLR9 agonists starts upstream of the targets of checkpoint inhibitors anti-PD-1/anti-PD-L1 a combinatory...
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634 Background: TLR9 agonists are potent activators of the immune system via induction of cellular and humoral responses. Preclinical and ongoing clinical studies support the use of TLR9 agonists for immunotherapeutic approaches.... more
634 Background: TLR9 agonists are potent activators of the immune system via induction of cellular and humoral responses. Preclinical and ongoing clinical studies support the use of TLR9 agonists for immunotherapeutic approaches. Lefitolimod/MGN1703 is a covalently-closed dumbbell-like immune surveillance reactivator (ISR) with a broad immunomodulatory potential. After promising data from a phase II trial (IMPACT) as maintenance therapy after first-line induction chemotherapy in patients with metastatic colorectal cancer lefitolimod is recently evaluated in a phase III trial in mCRC patients (IMPALA). Methods: It was previously shown that lefitolimod can reduce tumor growth in several murine tumor models. Since the mode-of-action of lefitolimod starts upstream of the initiation points of checkpoint inhibitors aCTLA-4 or aPD-1/aPD-L1 a combinatory approach may result in an enhanced anti-tumor effect. Therefore, we employed two syngeneic murine tumor models: One with s.c. inoculation ...
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Introduction: The use of TLR9 agonists as immunomodulators is supported by preclinical and clinical studies, showing their anti-tumor effect by enhancing both cellular and humoral responses. Two different families of DNA molecules... more
Introduction: The use of TLR9 agonists as immunomodulators is supported by preclinical and clinical studies, showing their anti-tumor effect by enhancing both cellular and humoral responses. Two different families of DNA molecules containing non-methylated CG-motifs for TLR9 activation have been established so far: Dumbbell-shaped dSLIM molecules are protected against exonucleolytic degradation by their covalently-closed, natural phosphodiester (PO) backbone. In contrast, single-stranded, oligodeoxynucleotides (CpG-ODN) are most commonly chemically-stabilized by phosphorothioates (PTO) in their phosphate moieties. However, PTO modifications produce off-target effects in immune cell populations and have resulted in an unfavorable risk-to-benefit ratio. Methods: Linear single-stranded ODN were synthesized using L-deoxyribonucleotides at their 3'-ends, which are the natural enantiomers of D-deoxyribonucleotides, to ensure protection against exonucleases and avoid the off-target eff...
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e15104 Background: The cell-based tumor vaccine MGN1601 for the treatment of renal cell carcinoma (RCC), consists of two active pharmaceutical ingredients: First, genetically modified allogeneic (human) cells in-vitro transiently... more
e15104 Background: The cell-based tumor vaccine MGN1601 for the treatment of renal cell carcinoma (RCC), consists of two active pharmaceutical ingredients: First, genetically modified allogeneic (human) cells in-vitro transiently transfected with four different MIDGE vectors encoding IL-7, GM-CSF, CD80 and CD154 and second, the synthetic DNA-based immunomodulatory molecule dSLIM-30L1, a TLR-9 agonist. The cells originate from primary RCC material. Methods: Studies of single-dose toxicity were performed with MGN1601 in rats (heterologous setting) by either subcutaneous or intradermal application (up to 300-fold or 60-fold of the amount of cells for patients/kg, respectively). Additionally, a single dose subcutaneous application of the murine homologue of MGN1601 in NMRI mice was performed (allogeneic setting, up to 2.900-fold of the amount of cells for patients/kg). Studies of repeated-dose toxicity (5- and 13-times, 28 days and 13 weeks, respectively) were performed in either the heterologous setting or t...
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680 Background: Patients with mCRC and disease control after induction with first-line chemotherapy +/- bevacizumab were included in the double-blind placebo-controlled phase II IMPACT trial, aiming to assess the clinical efficacy,... more
680 Background: Patients with mCRC and disease control after induction with first-line chemotherapy +/- bevacizumab were included in the double-blind placebo-controlled phase II IMPACT trial, aiming to assess the clinical efficacy, safety, and immunological effects of the immunomodulator MGN1703, a potent TLR9 agonist, given at the dose of 60 mg subcutaneously twice weekly as switch maintenance after first line induction therapy in mCRC. Methods: The trial was prematurely closed after randomization of 59 patients. The final analysis showed a superior effect of MGN1703 compared to placebo with hazard ratios (HR) for the primary endpoint PFS on maintenance of 0.55 (p=0.041) and 0.56 (p=0.070) by local investigator assessment or independent radiological review, respectively. Exploratory PFS analyses of pretreatment characteristics identified patients with normalized CEA, objective response, and the presence of activated NKT cells at the end of induction chemotherapy to benefit the most...
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633 Background: The synthetic DNA-based immunomodulator MGN1703 acts as an agonist of toll-like receptor 9. Based on promising data from a phase I study in patients with metastatic solid tumors including those with CRC, a phase II-III... more
633 Background: The synthetic DNA-based immunomodulator MGN1703 acts as an agonist of toll-like receptor 9. Based on promising data from a phase I study in patients with metastatic solid tumors including those with CRC, a phase II-III study was initiated in patients with advanced CRC having disease control after first-line therapy. The objective of the study is to assess efficacy and safety of the MGN1703 treatment in comparison to placebo. Methods: The IMPACT study is designed as a randomized double-blind placebo-controlled phase II-III study, which is conducted in patients with advanced CRC showing disease control after first-line therapy with standard chemotherapy regimen. The treatment is administered subcutaneously twice weekly in a ratio 2:1 (60 mg MGN1703 or placebo). The study is conducted in Germany, Austria, France, UK, Czech Republic and Russia, and 129 patients will be recruited into the study. The efficacy and safety of the study treatment will be evaluated based on ext...
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Background: The synthetic DNA-based immunomodulator MGN1703 is a member of the new dSLIM® family of TLR-9 agonists, comprising covalently closed dumbbell-like DNA molecules which consist entirely of natural DNA with two single-stranded... more
Background: The synthetic DNA-based immunomodulator MGN1703 is a member of the new dSLIM® family of TLR-9 agonists, comprising covalently closed dumbbell-like DNA molecules which consist entirely of natural DNA with two single-stranded CG-containing loops separated by a double-stranded stem. MGN1703 exerts its function by activating the innate and both arms of the adaptive immune system. MGN1703 has already shown a good safety profile and benefit for patients compared to placebo in maintenance therapy of metastatic colorectal carcinoma (mCRC) after fist-line induction therapy in a phase 2 clinical trial (MGN1703-C02, IMPACT). Methods: Following preclinical studies in mice and monkeys, a human clinical program was performed, including a phase 1 trial (MGN1703-C01), on a variety of solid tumors, and the double-blinded, placebo-controlled phase 2 IMPACT trial with mCRC patients. Additionally, a single dose crossover, placebo-controlled phase 1 cardiac safety trial, MGN1703-C04, was con...
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Background: In a first in men, proof-of-principle, multi-center, open-label, single-arm, non-randomized phase 1/2 clinical ASET trial (ClinicalTrials.gov: NCT01265368; EudraCT No.: 2009-016853-16) in patients with advanced RCC the tumor... more
Background: In a first in men, proof-of-principle, multi-center, open-label, single-arm, non-randomized phase 1/2 clinical ASET trial (ClinicalTrials.gov: NCT01265368; EudraCT No.: 2009-016853-16) in patients with advanced RCC the tumor vaccine MGN1601 has shown a good safety profile and improved overall survival in the per-protocol (PP) treated patient population. MGN1601 is a cell-based tumor vaccine consisting of two active pharmaceutical ingredients: Allogeneic (human) cells originating from renal cell carcinoma were gene-modified with four different MIDGE vectors encoding IL-7, GM-CSF, CD80 and CD154. These vaccine cells were combined with the synthetic DNA-based immunomodulator dSLIM®, a potent TLR-9 agonist. Methods: The tumor vaccine MGN1601 – each dose consists of 107 vaccine cells and 5 mg dSLIM® – was administered 8 times over 12 weeks with 3 weekly and 5 bi-weekly administrations (PP population) in the ASET trial. Specific humoral immune responses in sera from patients b...
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Deoxyribonucleic acid (DNA) vaccines are used for experimental immunotherapy of equine melanoma. The injection of complexed linear DNA encoding interleukin (IL)-12/IL-18 induced partial tumour remission in a clinical study including 27... more
Deoxyribonucleic acid (DNA) vaccines are used for experimental immunotherapy of equine melanoma. The injection of complexed linear DNA encoding interleukin (IL)-12/IL-18 induced partial tumour remission in a clinical study including 27 grey horses. To date, the detailed mechanism of the anti-tumour effect of this treatment is unknown. In the present study, the clinical and cellular responses of 24 healthy horses were monitored over 72 h after simultaneous intradermal and intramuscular application of equine IL-12/IL-18 DNA (complexed with a transfection reagent) or comparative substances (transfection reagent only, nonsense DNA, nonsense DNA depleted of CG). Although the strongest effect was observed in horses treated with expressing DNA, horses in all groups treated with DNA showed systemic responses. In these horses treated with DNA, rectal temperatures were elevated after treatment and serum amyloid A increased. Total leukocyte and neutrophil counts increased, while lymphocyte num...
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The aim of this study was the development of a fast and reliable polymerase chain reaction (PCR) assay which quantifies the proportion of human cells in immunodeficient chimeric mice, for example transplanted with human hematopoietic stem... more
The aim of this study was the development of a fast and reliable polymerase chain reaction (PCR) assay which quantifies the proportion of human cells in immunodeficient chimeric mice, for example transplanted with human hematopoietic stem cells. We developed a TaqMan chemistry-based, real-time duplex PCR assay to quantify human and murine DNA in a single-tube reaction in parallel (HUmu PCR). Two independent sets of primers and exonuclease probes, located in the tumor necrosis factor-a gene of both species, were selected to amplify specifically human and murine genomic DNA. Serial dilutions of defined numbers of human cells in mouse cells served to construct calibration curves. The test was applied to NOD/SCID mice transplanted with CD34(+) cells isolated from human cord blood and compared to FACS analysis. Analysis of DNA from human cells diluted stepwise into a fixed number of murine cells - and vice versa - led to calibration curves with good correlation for human and murine cells...
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p53 is the most frequently mutated gone in human cancer cells. Its wild-type gone encodes for a protein with pivotal functions: (i) interaction with key players in the cell cycle leading to cell cycle arrest; (ii) induction of programmed... more
p53 is the most frequently mutated gone in human cancer cells. Its wild-type gone encodes for a protein with pivotal functions: (i) interaction with key players in the cell cycle leading to cell cycle arrest; (ii) induction of programmed call death, or apoptosis. P53 may be seen as another member of the family of proteins involved in resistance to anticancer therapy, since mutations/deletions involving the p53 gene lead frequently to resistance of radiation/cytotoxic drug treatment. Consequently, patients with p53-mutated tumors may harbor a worse prognosis. On the other hand, reintroducing wild-type P53 may lead to an adequate function of the cellular cell cycle and/or apoptosis program, thus enabling efficient anti-cancer therapy even in the presence of mutated P53. Two options are being discussed: (i) gene therapy approaches; (ii) modulating mutated P53 with yet unknown molecules.
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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... more
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...
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ABSTRACT Background Study results demonstrated that IFN augments BEV activity and improves median PFS in pts with mRCC. Thus, combination BEV + IFN is a standard first-line treatment option for mRCC. Combining BEV with the mTOR inhibitor... more
ABSTRACT Background Study results demonstrated that IFN augments BEV activity and improves median PFS in pts with mRCC. Thus, combination BEV + IFN is a standard first-line treatment option for mRCC. Combining BEV with the mTOR inhibitor EVE may be an efficacious and well-tolerated treatment option. The open-label, phase II RECORD-2 trial compared first-line EVE + BEV and IFN + BEV in mRCC. Patients and methods: Therapy-naive pts with clear cell mRCC and prior nephrectomy were randomized 1:1 to BEV 10 mg/kg IV every 2 weeks with either EVE 10 mg oral daily or IFN (9 MIU SC 3 times/week, if tolerated). Tumour assessments were every 12 weeks. Primary objective was treatment effect on progression-free survival (PFS) per central review based on an estimate of the chance of a subsequent phase III trial success (50% threshold for phase II success). Results In EVE + BEV (n = 182) and IFN + BEV (n = 183) arms, median age was 60/60 years, 76/72% of pts were men, MSKCC risk was favourable/intermediate/poor in 36/57/7% and 36/57/7% of pts, and 43/46% of pts had >2 organs involved, respectively. For EVE + BEV and IFN + BEV, median treatment duration was 8.5/8.3 months, respectively; 23/26% of pts discontinued due to AEs. In EVE + BEV and IFN + BEV arms, median PFS by central review was 9.3/10.0 months (HRIFN/EVE, 0.91; 95% CI, 0.69-1.19; P =0.485), respectively; probability of subsequent phase III success was 5.1%. Results of central and local PFS analysis were consistent. Objective response rate was 27/28% in EVE + BEV and IFN + BEV arms, respectively. Median overall survival (OS) was not reached in the EVE + BEV arm and was 25.9 months (95% CI: 21.1, 30.2) in the IFN + BEV arm. Most frequent AEs (%) were stomatitis (63), proteinuria (49), diarrhoea (39), hypertension (38), and epistaxis (35) in EVE + BEV arm and decreased appetite (45), fatigue (41), proteinuria (37), and pyrexia (35) in IFN + BEV arm. Conclusions In RECORD-2, PFS and tolerability were similar for first-line EVE + BEV and IFN + BEV. Final OS analysis will occur after 2-year follow-up. Disclosure A. Ravaud: Alain Ravaud is a member of global, European, and/or French boards on urological tumors for Pfizer, Novartis, GlaxoSmithKline, Bayer-Schering, and Dendreon, and has received institutional grant support from Pfizer, Novartis, and Roche. O. Anak: Ozlem Anak is an employee of Novartis Pharma AG. D. Pelov: Diana Pelov is an employee of Novartis Pharmaceuticals Corporation. A. Louveau: Anne-Laure Louveau is an employee of Novartis Pharma S.A.S. T. M-H: Tay M-H is a speaker for an advisory board for Novartis Pharmaceuticals Corporation. B. Melichar: Bohuslav Melichar has received honoraria from Novartis and Roche and served on an advisory board for Roche. All other authors have declared no conflicts of interest.
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Purpose: We conducted a phase I/II randomized trial to evaluate the clinical and immunologic effect of chemotherapy combined with vaccination in primary metastatic colorectal cancer patients with a carcinoembryonic antigen–derived peptide... more
Purpose: We conducted a phase I/II randomized trial to evaluate the clinical and immunologic effect of chemotherapy combined with vaccination in primary metastatic colorectal cancer patients with a carcinoembryonic antigen–derived peptide in the setting of adjuvants granulocyte macrophage colony-stimulating factor, CpG-containing DNA molecules (dSLIM), and dendritic cells. Experimental Design: HLA-A2–positive patients with confirmed newly diagnosed metastatic colorectal cancer and elevated serum carcinoembryonic antigen (CEA) were randomized to receive three cycles of standard chemotherapy (irinotecan/high-dose 5-fluorouracil/leucovorin) and vaccinations with CEA-derived CAP-1 peptide admixed with different adjuvants [CAP-1/granulocyte macrophage colony-stimulating factor/interleukin-2 (IL-2), CAP-1/dSLIM/IL-2, and CAP-1/IL-2]. After completion of chemotherapy, patients received weekly vaccinations until progression of disease. Immune assessment was done at baseline and after three ...
Research Interests: Immunology, Flow Cytometry, Colorectal cancer, Humans, Internal Medicine, and 15 moreFemale, Male, Immunotherapy, Aged, Adult, Camptothecin, Carcinoembryonic Antigen, Interleukin, Interferon gamma, Colorectal Neoplasms, Leucovorin, Combined Modality Therapy, Chemoimmunotherapy, Liver neoplasms, and fluorouracil
3643 Background: Standard induction chemotherapy for mCRC is often discontinued in patients responding to the treatment. MGN1703, a synthetic DNA-based immunomodulator, acts as TLR-9 agonist. This trial has been conducted to assess... more
3643 Background: Standard induction chemotherapy for mCRC is often discontinued in patients responding to the treatment. MGN1703, a synthetic DNA-based immunomodulator, acts as TLR-9 agonist. This trial has been conducted to assess clinical efficacy, safety, and immunogenicity of MGN1703 as maintenance therapy vs placebo. Methods: The IMPACT trial is an international, multicenter, randomized (2:1) double-blind placebo-controlled phase 2 trial in mCRC patients with disease control (CR, PR, SD) after 4.5 to 6 months of 1st-line induction chemotherapy with FOLFOX/XELOX or FOLFIRI +/- bevacizumab. Results: 59 patients have been randomized (43 MGN1703, 16 placebo). Median PFS from start of maintenance was not different with 2.8 vs 2.7 months, however the HR was 0.56 (CI 95%: 0.29-1.08; p=0.069) in favor of MGN1703, due to a small favorable subgroup with long-term PFS (20% vs 0% at 9 months; p=0.006). Total PFS from beginning of induction chemotherapy including maintenance was significantly improved: HR 0.49 (CI 95%: 0.25-0.94), p=0.029. After a median follow-up of 13 months 66% of patients are still alive (67% vs 62%), therefore survival data are still preliminary (HR 0.79; CI 95%: 0.3-2.1) and will be mature at the meeting. Activation of cellular immune function as indicated by significant increase of CD14+CD169+monocytes was observed in all but one of the MGN1703 treated patients, while absent in all placebo patients. Treatment was well tolerated: 46.5% vs 31.3% of patients (MGN1703 vs placebo) had any drug-related adverse events (AE) and 20.9% vs 18.8% had AE with grade 3 or 4 (including hypertension, ileus, sepsis, sensory polyneuropathy, nausea/vomiting for MGN1703 and pain, popular exanthema for placebo). Conclusions: MGN1703 maintenance seems to prolong PFS in a subgroup of patients with disease control after induction chemotherapy vs placebo, and is associated with relative mild toxicity. This in an early signal in a selected and very limited patient population which supports further investigation. Predictive biomarkers are under evaluation to identify a potential subgroup which might have benefit from this TLR-9 MGN1703 maintenance. Clinical trial information: NCT01208194.
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ABSTRACT Heterotrimeric guanosine triphosphate (GTP)-binding proteins (G proteins) act as transducers and amplifiers between activated heptahelical membrane receptors and effector systems such as enzymes, ion channels, and transporters to... more
ABSTRACT Heterotrimeric guanosine triphosphate (GTP)-binding proteins (G proteins) act as transducers and amplifiers between activated heptahelical membrane receptors and effector systems such as enzymes, ion channels, and transporters to mediate signals from the outside to inside of cells. The G-protein subtypes are defined by the a-subunits, of which 23 are known by now. Functional, active heterotrimeric G proteins include β- and γ-subunits as well. Currently, at least five different β- and 11 different γ-subforms are known (for review, see ref. 1) In many cases, the coupling between receptor and G protein is not selective; one given receptor activates more than one G protein and thus mitiates more than one signal-transduction pathway. On the other hand, there are numerous examples showing that different receptors activate one type of G protein to regulate the same effector system; e.g., there is inhibition of voltagegated calcium channels by various hormones in neuronal and endocrine cells via G0 (for review, see ref. 2). In all cases, the question arises whether the different receptors recognize the same heterotrimeric G proteins or whether the receptors see different specific heterotrimers, varying in the subform composition of the β- and γ-subunits. Free combmation between all subforms of G-protein subunits would result in several hundreds of specific heterotrimers.
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Research Interests: Oncology, Medicine, Population, Internal Medicine, Placebo, and 4 moreBevacizumab, Irinotecan, FOLFIRI, and hazard ratio
e14625 Background: TLR9 agonists are potent activators of the immune system via induction of cellular and humoral responses. Preclinical and ongoing clinical studies support the use of TLR9 agonists for immunotherapeutic approaches.... more
e14625 Background: TLR9 agonists are potent activators of the immune system via induction of cellular and humoral responses. Preclinical and ongoing clinical studies support the use of TLR9 agonists for immunotherapeutic approaches. Lefitolimod/MGN1703 is a covalently-closed dumbbell-like immune surveillance reactivator (ISR) with a broad immunomodulatory potential. Due to promising data from a phase 2 trial (IMPACT) as maintenance therapy after first-line chemotherapy in mCRC patients lefitolimod is recently evaluated in a phase 3 trial in mCRC patients (IMPALA). Furthermore, lefitolimod is currently investigated in a phase 2 trial in SCLC patients (IMPULSE) and in a phase 1 / 2 trial in HIV patients (TEACH). Methods: It was shown that lefitolimod reduces tumor growth in several murine tumor models. Since the mode-of-action of lefitolimod starts upstream of the initiation points of checkpoint inhibitors like anti-CTLA-4 or anti-PD-1/anti-PD-L1 a combinatory approach may result in an enhanced anti-tumor effect. Therefore, two syngeneic murine models were used – a colon carcinoma CT26 and a lymphoma A20 model – for evaluation of the anti-tumor effect in vivo. Results: In the CT26 model treatment with anti-PD-L1 (i.p.) had no effect on the tumor growth, whereas addition of lefitolimod (s.c.) to anti-PD-L1 led to an anti-tumor effect (tumor growth inhibition, TGI 48%) which consequently resulted in prolonged survival of the mice. This combinatory effect was even more pronounced in the A20 model where treatment with anti-PD-1 (i.p.) alone had a moderate anti-tumor effect which was vastly increased by the combination (TGI – anti-PD-1: 46%, anti-PD-1/lefitolimod 99%). Conclusions: In conclusion, we showed that lefitolimod, a member of dSLIM® family of TLR9 agonists and an ISR, can enhance the limited anti-tumor effects of checkpoint inhibitors in pilot studies in murine colon carcinoma and lymphoma tumor models in vivo. These data show the promising potential for the combination with checkpoint inhibitors. Notably, a clinical trial in cooperation with MD Anderson evaluating the benefit of lefitolimod in combination with ipilimumab is currently ongoing.
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3267 Polychemotherapy has dramatically improved the outcome of patients with acute lymphoblastic leukemia (ALL) and leads to long term remission in 70–80 % of children and 40–50% of adults. However, it is likely that after remission the... more
3267 Polychemotherapy has dramatically improved the outcome of patients with acute lymphoblastic leukemia (ALL) and leads to long term remission in 70–80 % of children and 40–50% of adults. However, it is likely that after remission the immune system plays an essential part in the eradication of minimal residual disease. Since chemotherapy compromises the immune system, compounds without immunosuppressant activity should be developed for maintenance therapy in order to reduce the relapse rate. Anthocyanins are a group of naturally occurring phenolic compounds widely available in fruits and vegetables in human diets. They have broad biological activities including antimutagenesis and anticarcinogenesis, which are generally attributed to their antioxidant activities. We studied the effects and the mechanisms of anthocyanin-rich berry extract and the most common types of anthocyanins, cyanidin-3-rutinoside and dephinidin, in several leukemia cell lines. Proliferation was significantly ...
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3615 Background: The immunomodulator MGN1703, a TLR-9 agonist, has shown good safety profile in patients with metastatic solid tumors. The IMPACT trial was conducted to assess clinical efficacy, safety, and immunological effects of... more
3615 Background: The immunomodulator MGN1703, a TLR-9 agonist, has shown good safety profile in patients with metastatic solid tumors. The IMPACT trial was conducted to assess clinical efficacy, safety, and immunological effects of MGN1703 as maintenance therapy twice weekly. Methods: The international randomized (2:1) double-blind placebo-controlled phase 2 IMPACT trial in mCRC patients with disease control after 1st-line chemotherapy by FOLFOX/XELOX or FOLFIRI +/- bevacizumab. After randomization of 59 out of 129 planned patients (43 MGN1703, 16 placebo) the trial was prematurely closed due to slow recruitment. Results: A superior effect of MGN1703 compared to placebo was shown: HR for the primary endpoint PFS on maintenance was 0.55 (p=0.041) by local and 0.56 (p=0.070) by independent assessment. For PFS from start of induction therapy the HR was 0.50 (p=0.022) and 0.49 (p=0.030), respectively. Notably, at time of study closure 4 MGN1703 patients were still free of PD and continued in compassionate use...
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Research Interests: Molecular Biology, Biology, Medicine, Biological Sciences, Cell line, and 15 moreAnimals, Calcium channels, Pituitary Gland, Cell nucleus, G protein, Amino Acid Sequence, Base Sequence, Barium Compounds, Gtp Binding Proteins, Galanin, islets of Langerhans, Calcium Channel Blockers, Chlorides, Molecular Sequence Data, and Medical and Health Sciences
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e15067 Background: MGN1601 is a cell-based tumor vaccine for the treatment of mRCC. MGN1601 consists of two active pharmaceutical ingredients. One consists of allogeneic, human tumor cells, derived...
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Modulation of voltage-gated Ca2+ channels by hormones and neurotransmitters provides a common mechanism for regulation of cellular functions. During the last decade, the understanding of the underlying biochemical pathways has largely... more
Modulation of voltage-gated Ca2+ channels by hormones and neurotransmitters provides a common mechanism for regulation of cellular functions. During the last decade, the understanding of the underlying biochemical pathways has largely progressed (for recent overviews see Birnbaumer 1990, Birnbaumer et al. 1991; Schultz et al. 1990). Here we give a brief report of our work on the hormonal inhibition of Ca2+ currents in neuronal and endocrine cells. Additional informations on this field will be given by H.D. Lux, A.M.Brown and E. Carbone in this volume.
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ABSTRACT A given heptahelical receptor uses a limited set of G proteins to interact with and to affect a given effector system. It was assumed that the specificity in receptor-G protein-effector coupling is only determined by the α... more
ABSTRACT A given heptahelical receptor uses a limited set of G proteins to interact with and to affect a given effector system. It was assumed that the specificity in receptor-G protein-effector coupling is only determined by the α subunit of the G protein, but a large body of evidences supports the idea that in addition to the α subunits the βγ dimers determine G-protein specificity. We focus to the question how the antisense technology can be used to determine the identity of individual subtypes of G protein subunits involved in signal transduction cascades.
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Abstract 4730 Background The DNA-based immunomodulator MGN1703 stimulates the innate and cellular immune system mainly via the TLR9-receptor. The results of the recent in vivo experiments showed potent anti-tumor efficacy of MGN1703 in... more
Abstract 4730 Background The DNA-based immunomodulator MGN1703 stimulates the innate and cellular immune system mainly via the TLR9-receptor. The results of the recent in vivo experiments showed potent anti-tumor efficacy of MGN1703 in several mouse tumor models in prophylactic and therapeutic settings as well as a good safety profile in various animals. Two investigator-initiated pilot trials of MGN1703 as adjuvant in patients with metastatic solid tumors also showed good safety and tolerability of the drug as well as a positive effect on the response rate in patients treated with MGN1703. Patients/Methods In this Phase 1 clinical trial MGN1703 is administered subcutaneously in escalating doses (0.25 mg, 2 mg, 10 mg, 30 mg, and 60 mg; 3-6 patients per group) either in a single or in a multiple (2x / week over 6 weeks) dose regimen. Patients with metastatic tumors of the following entities are recruited for the study, if no other standard treatment options are available: Colorectal cancer, breast cancer, lung cancer, renal cell carcinoma and melanoma. Primary endpoints are evaluation of the safety and tolerability of escalating single doses and of escalating multiple doses of s.c. administered MGN1703, determination of the maximum tolerated dose (MTD) and dose limiting toxicity (DLT), and recommendation of a dose for a Phase 2 trial in patients. Results Currently, 12 patients have been treated and evaluated in the single dose groups of 0.25 mg, 2 mg, 10 mg and 30 mg (3 patients each). In the multiple dose group, 4 patients have been treated with 0.25 mg, 3 patients with 2 mg, 3 patients with 10 mg and 3 patients with 30 mg MGN1703, so far. Therapy was well tolerated except for sporadic transient symptoms as mild redness and induration of injection sites in two patients, increase of temperature to 38 °C in one patient, and fatigue in two patients. In the 0.25 mg group, one patient showed a stable disease (SD, according to RECIST) after 6 weeks of treatment, and in the 2 mg group, 3 of 3 patients showed a SD after 6 weeks. Treatment results of the last 2 dosing groups are pending. The four patients, who responded to the treatment with MGN1703, were treated with MGN1703 for further 6 weeks within an extension phase of this clinical trial. Two of them still had a SD after 12 weeks of treatment. Conclusions MGN1703 showed safety and tolerability at dosages up to 30 mg so far. The detailed evaluation of clinical and immunological responses is still ongoing. There has been no DLT at this point of the Phase 1 trial. Disclosures: Weihrauch: MOLOGEN AG: Membership on an entity's Board of Directors or advisory committees. Schmidt:MOLOGEN AG: Employment. Tschaika:MOLOGEN AG: Employment. Wittig:MOLOGEN AG: Membership on an entity's Board of Directors or advisory committees.
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392 Background: MGN1601 is a cell-based RCC tumor vaccine MGN1601 consisting of two active pharmaceutical ingredients: genetically modified allogeneic (human) cells transfected with four different MIDGE vectors encoding IL-7, GM-CSF, CD80... more
392 Background: MGN1601 is a cell-based RCC tumor vaccine MGN1601 consisting of two active pharmaceutical ingredients: genetically modified allogeneic (human) cells transfected with four different MIDGE vectors encoding IL-7, GM-CSF, CD80 and CD154 and a synthetic DNA-based immunomodulator dSLIM-30L1, a TLR-9 agonist. The vaccine is being developed for treatment of patients with advanced RCC. Its prophylactic and therapeutic anti-tumor activity has been shown in several in-vivo models. A good safety profile of MGN1601 was shown in a wide program of acute and chronic toxicity studies. Based on these promising data, this phase 1/2 study was started in patients with advanced RCC. Methods: This multicentric open clinical study for the assessment of safety and efficacy of MGN1601 in patients with advanced RCC was initiated in October 2010. A total of 24 patients have to be recruited into the study. The treatment consists of 8 MGN1601 treatments administered as follows: the first 3 treatm...
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Research Interests: Gastroenterology, Treatment, Treatment Outcome, STEROIDS, Medicine, and 15 moreProspective studies, Humans, Internal Medicine, Female, Male, Clinical Sciences, Adult, Methotrexate, Combination drug therapy, Long Term, Cyclophosphamide, Crohn Disease, Azathioprine, Immunosuppressive Agents, and Pharmacology and pharmaceutical sciences
Research Interests: Immune response, Biology, Medicine, Gene expression, Biological Sciences, and 15 moreHumans, Mice, Animals, Immunization, DNA vaccines, DNA vaccination, HeLa cells, Cutaneous Leishmaniasis, DNA vaccine, Protozoan Proteins, Plasmid, Leishmania Major, Plasmid DNA, Nuclear localization signal, and Medical and Health Sciences
Linear, single-stranded oligonucleotides (ODN) with non-methylated cytosine-guanine (CpG) motifs are immunomodulatory since they resemble bacterial DNA and serve as “danger signals”. These CpG-ODNs promote predominately a TH1-response,... more
Linear, single-stranded oligonucleotides (ODN) with non-methylated cytosine-guanine (CpG) motifs are immunomodulatory since they resemble bacterial DNA and serve as “danger signals”. These CpG-ODNs promote predominately a TH1-response, with secretion of IL-12 and IFN-γ, and B-cell, natural killer (NK)-cell and dendritic cell (DC) activation and have a broad potential as therapeutic agents, i.e. for cancer gene therapy and for the treatment of allergic diseases. Distinct groups of CpG-ODNs were characterized differing in structure and function: one group promotes B-cell proliferation, monocyte stimulation and secretion of IgM and IL-6; another activates plasmacytoid DC to produce IFN-α/-β and thus γδT-cells and NK-cells to express CD69 and secrete IFN-γ. And a third group exhibits combined properties of stimulating IL-6 and IgM secretion from B cells as well as IFN-α production from pDCs. Phosphorothioate (PS) modifications, usually introduced to enhance stability, result in several ...