Application of <i>in vivo</i> imaging techniques to monitor therapeutic efficiency of PLX4720 in an experimental model of microsatellite instable colorectal cancer

Rohde, Sarah L.; Lindner, Tobias; Polei, Stefan; Stenzel, Jan; Borufka, Luise; Achilles, Sophie; Hartmann, Eric; Lange, Falko; Maletzki, Claudia; Linnebacher, Michael; Glass, Änne; Schwarzenböck, Sarah M.; Kurth, Jens; Höhn, Alexander; Vollmar, Brigitte; Krause, Bernd J.; Jaster, Robert

doi:10.18632/oncotarget.19263

Cited by 13 publications

(10 citation statements)

References 28 publications

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“…Therapeutic lysate application in GIT-bearing MLH1 ¡/¡ mice significantly prolonged survival. PET/CT imaging with 18 F-FDG, a sensitive parameter to monitor treatment response, 29 confirmed vaccination-induced disease control with some tumor nodules even completely disappearing within four weeks. Immune responses, characterized by elevated numbers of cytotoxic T and NK cells as well as specific recognition of MLH1 ¡/¡ GIT target cells by lymphocytes from vaccinated mice accompanied the therapeutic response.…”

Section: E1408748-8mentioning

confidence: 71%

“…Therapeutic vaccinations started after in vivo confirmation of GI tumor growth, as determined by small animal PET/CT imaging. 29 Mice received four weekly injections of the vaccine (10 mg/kg bw, s.c.) again with or without CpG ODN 1826 (2.5 mg/kg bw, s.c., n D 9 and n D 7, respectively), followed by biweekly applications of the lysate only (2.5 mg/kg bw) until tumor progression. PET/CT imaging was repeated on day 28 of therapy.…”

Section: Mlh1 ¡/¡ Mouse Model and Vaccine Preparationmentioning

confidence: 99%

“…During measurement animals were kept at constant temperature of 38 C by an electrical heating pad and respiration was monitored. 29 CT images were reconstructed with a Feldkamp algorithm. PET data were first Fourier rebinned into a 2D dataset from which real-space images were reconstructed with an ordered subset expectation maximization (OSEM) algorithm with 16 subsets and four iterations.…”

Section: Pet/ct Imagingmentioning

confidence: 99%

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Cellular vaccination of MLH1^−/− mice – an immunotherapeutic proof of concept study

et al. 2017

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Mismatch-repair deficiency (MMR-D) is closely linked to hypermutation and accordingly, high immunogenicity. MMR-D-related tumors thus constitute ideal vaccination targets for both therapeutic and prophylactic approaches. Herein, the prophylactic and therapeutic impact of a cellular vaccine on tumor growth and tumor-immune microenvironment was studied in a murine MLH1 knockout mouse model. Prophylactic application of the lysate (+/- CpG ODN 1826) delayed tumor development, accompanied by increased levels of circulating T cell numbers. Therapeutic application of the vaccine prolonged overall survival (median time: 11.5 (lysate) and 12 weeks (lysate + CpG ODN) vs. 3 weeks (control group), respectively) along with reduced tumor burden, as confirmed by PET/CT imaging and immune stimulation (increased CD3CD8 T - and NK cell numbers, reduced levels of TIM-3 cells in both treatment groups). Coding microsatellite analysis of MMR-D-related target genes revealed increased mutational load upon vaccination (total mutation frequency within 28 genes: 28.6% vaccine groups vs. 14.9% control group, respectively). Reactive immune cells recognized autologous tumor cells, but also NK cells target YAC-1 in IFNγ ELISpot and, even more importantly, in functional kill assays. Assessment of tumor microenvironment revealed infiltration of CD8 T-cells and granulocytes, but also upregulation of immune checkpoint molecules (LAG-3, PD-L1). The present study is the first reporting results on a therapeutic cellular MMR-D vaccine. Vaccination-induced prolonged survival was achieved in a clinically-relevant mouse model for MMR-D-related diseases by long-term impairment of tumor growth and this could be attributed to re-activated immune responses.

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Section: E1408748-8mentioning

confidence: 71%

Section: Mlh1 ¡/¡ Mouse Model and Vaccine Preparationmentioning

confidence: 99%

Section: Pet/ct Imagingmentioning

confidence: 99%

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Cellular vaccination of MLH1^−/− mice – an immunotherapeutic proof of concept study

et al. 2017

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“…CT images were reconstructed with Feldkamp algorithm. PET data were first Fourier rebinned into 41 a 2D dataset from which real-space images were reconstructed with an ordered subset expectation maximization (OSEM) algorithm with 16 subsets and 4 iterations 41 , 42 . Data were decay-corrected to the time of injection.…”

Section: Methodsmentioning

confidence: 99%

Anatomical MRI and [18F]FDG PET/CT imaging of Schistosoma mansoni in a NMRI mouse model

Lindner

Stenzel

Koslowski

et al. 2020

Sci Rep

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Schistosomiasis represents one of the most devastating worm parasitosis in the world. Current diagnostic methods are insufficient to determine the infection grade and the disease related organ damage. We herein investigated whether discrimination of infection grade and its correlation to liver damage could be accurately performed by multimodal imaging in a mouse model of Schistosoma mansoni infection. Therefore, groups of uninfected and infected mice underwent MRI and [18F]FDG PET/CT imaging. Anatomical MRI images were used for liver volumetry and for quantification of hepatic granulomas. For PET/CT images a volume of interest based analyses were employed to calculate the [18F]FDG uptake in liver, portal vein, spleen and abdomen. Herein, we demonstrate that the combined use of [18F]FDG-PET/CT and MRI represents an appropriate diagnostic tool for Schistosoma mansoni infection, but fails to discriminate the infection grade and the linked organ damage. Only the splenic [18F]FDG uptake in the 25 cercariae group (5.68 ± 0.90%ID/cc) and 50 cercariae group (4.98 ± 1.43%ID/cc) was significantly higher compared to the control group (2.13 ± 0.69%ID/cc). Nevertheless, future multimodal imaging studies with new radiopharmaceuticals could build a highly sensitive and specific basis for the diagnosis and evaluation of organ damage of schistosomiasis.

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“…PET/CT imaging PET/CT imaging scans were performed on a small animal PET/CT scanner (Inveon PET/CT, Siemens Medical Solutions, Knoxville, TN, USA) according to a standard protocol as described before [29,30].…”

Section: Experimental Protocolmentioning

confidence: 99%

Combined Vaccine-Immune-Checkpoint Inhibition Constitutes a Promising Strategy for Treatment of dMMR Tumors

Salewski

Kuntoff

Kuemmel

et al. 2020

Preprint

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Background: Mlh1-knock-out-driven mismatch-repair-deficient (dMMR) tumors can be targeted immunologically. By applying therapeutic tumor vaccination, tumor growth is delayed but escape mechanisms evolve, characterized by the upregulation of immune-checkpoint molecules (LAG-3, PD-L1). To counteract immune escape, we investigated the therapeutic activity of a combined tumor vaccine-immune checkpoint inhibitor therapy using α-PD-L1 monoclonal antibody clone 6E11.Design: In this trial, Mlh1-knock-out mice with established gastrointestinal tumors received single or thrice injections of α-PD-L1 monoclonal antibody clone 6E11 (2.5 mg/kg bw, q2w, i.v.) either alone or in combination with the vaccine. Longitudinal flow cytometry and PET/CT imaging studies were followed by ex vivo functional immunological and gene expression assays.Results: 6E11 monotherapy slightly increased median overall survival (mOS: 6.0 weeks vs. control 4.0 weeks). Increasing the number of injections (n=3) improved therapy outcome (mOS: 9.2 weeks) and was significantly boosted by combining 6E11 with the vaccine (mOS: 19.4 weeks vs. 10.2 weeks vaccine monotherapy). Accompanying PET/CT imaging confirmed treatment-induced tumor growth control, with the strongest inhibition in the combination group. Three mice (30%) achieved a complete remission and showed long-term survival. Decreased levels of circulating splenic and intratumoral myeloid-derived suppressor cells (MDSC) and decreased numbers of immune-checkpoint-expressing splenic T cells (LAG-3, CTLA-4) accompanied therapeutic effects. Gene expression and protein analysis of residual tumors revealed downregulation of PI3K/Akt/Wnt and TGF-signaling, leading to T cell infiltration and reduced numbers of macrophages, neutrophils, and MDSC.Conclusions: By successful uncoupling of the PD-1/PD-L1 axis, we provide further evidence for the safe and successful application of immunotherapies to combat dMMR-driven malignancies that warrants further investigation.

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Application of in vivo imaging techniques to monitor therapeutic efficiency of PLX4720 in an experimental model of microsatellite instable colorectal cancer

Cited by 13 publications

References 28 publications

Cellular vaccination of MLH1^−/− mice – an immunotherapeutic proof of concept study

Cellular vaccination of MLH1^−/− mice – an immunotherapeutic proof of concept study

Anatomical MRI and [18F]FDG PET/CT imaging of Schistosoma mansoni in a NMRI mouse model

Combined Vaccine-Immune-Checkpoint Inhibition Constitutes a Promising Strategy for Treatment of dMMR Tumors

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Application of in vivo imaging techniques to monitor therapeutic efficiency of PLX4720 in an experimental model of microsatellite instable colorectal cancer

Cited by 13 publications

References 28 publications

Cellular vaccination of MLH1−/− mice – an immunotherapeutic proof of concept study

Cellular vaccination of MLH1−/− mice – an immunotherapeutic proof of concept study

Anatomical MRI and [18F]FDG PET/CT imaging of Schistosoma mansoni in a NMRI mouse model

Combined Vaccine-Immune-Checkpoint Inhibition Constitutes a Promising Strategy for Treatment of dMMR Tumors

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Cellular vaccination of MLH1^−/− mice – an immunotherapeutic proof of concept study

Cellular vaccination of MLH1^−/− mice – an immunotherapeutic proof of concept study