3rd FORUM Science & Health
July 5-6, 2022
Day 1: July 5, from 12:45 - 13:30 and 15:45 - 16:15
Day 2: July 6, from 12:00 - 12:30
The Poster award ceremony will take place during the closing session on
July 6, 15:00-15:30.
Frank Staubli1, Pavel Honsa2, Jana Sponarova1, Jean-Marie Droz1, Stefan Bleuler1, Philip Zimmermann1
GENEVESTIGATOR® is a high-performance knowledge-base and analysis tool for gene expression data. lt integrates thousands of manually curated public transcriptomic studies from human or model organisms, while enabling effective visualization of gene expression across different biological contexts such as diseases, drug treatments, tissues, cancers, cell lines, or genotypes.
The recent exponential increase of publicly available single-cell RNA-Seq studies and the power of this technology for de novo discoveries prompted us to build a manually curated and globally normalized single-cell RNA-Seq compendium.
Here, we present the steps of our curation pipeline, and demonstrate an example analysis in GENEVESTIGATOR® for identifying cell-type specific responses to COVID-19 using a published 10x single-cell RNA-Seq study.
T. J. Strzalkowski1, B. L. Cadilha1,I. Dalloul1, K. Manske1, S. Endres1,2,3, S. Kobold1,2,3
Chimeric antigen receptor (CAR) T cells have shown great efficacy in treating hematological malignancies. Nonetheless, in solid tumors CAR T cells have yet to demonstrate significant clinical efficacy. In solid tumors, CAR T cells are frequently prevented access to tumor tissue and face profound suppression at the tumor site. To overcome this issue, our group could previously demonstrate that arming CAR T cells with C-C-motive-receptor 8 for improved tumor-directed migration along the C-C-chemokine ligand 1 - CCR8 axis and a dominant-negative receptor against TGF-β for resistance to suppression enable activity in pancreatic cancer models. The value of this approach for other entities was however unclear. We now investigated the potential of this combination for treatment of HER2-positive cancer models in conjunction with a HER2-targeted CAR.
Materials and methods:
Primary murine and human T cells were isolated and activated. T cells were retrovirally transduced. Phenotype, activation, exhaustion and proliferation were monitored in vitro. Cytokine production was assessed with ELISA. In vivo, survival and tumor growth of mice that were subcutaneously injected with tumor cells and treated with CAR T cells carrying either CCR8, DNR or both receptors were measured. To look at chemokine expression in tumor material, mRNA was isolated from tumor material and RT-qPCR was performed. Results: We found that expression of CCR8 can redirect CAR T cells to the tumor and a DNR can prevent immunosuppression of CAR T cells in the tumor microenvironment. The improved functionality of CAR-CCR8-DNR T cells compared to CAR T cells against the HER2 antigen could be demonstrated in vitro and in vivo in human HER2+ tumor models.
Equipping CAR T cells with CCR8 and DNR emerges as a strategy not only limited to certain antigens, but as a potential universal approach to render cellular therapies more effective. The modularity of this concept promises further preclinical and perhaps clinical development to improve personalized immunotherapy.
Thomas Heinrich1, Ingo Schubert2, Michael Aigner3, Georg Fey1
KOSMAS Therapeutics, a spin-off from the Univ. of Erlangen-Nuremberg (FAU), develops new tri-specific immuno-therapeutic agents for the treatment of cancer in the patent-protected "Trilyte" format. MISSION: To reach prolonged survival and a better Quality of Life for cancer patients through improved elimination of cancer stem cells (CSCs), the source of relapsed and metastatic disease. UNIQUE CAPA-BILITIES: The new binding mode of "dual targeting" differentiates trilytes from com-peting agents, which mostly bind only 1 type of target on a cancer cell. One trilyte molecule simultaneously binds 2 different targets on the same cancer cell and uses its third binding domain to engage a killer cell. "Dual-targeting" enables an enhan-ced "selectivity of lysis". A suitably chosen pair of target antigens allows trilytes to discriminate better than mono-targeting agents between CSCs, bulk cancer cells and corresponding normal cells. Kosmas' lead agent KT-1 engages NK cells, which have a favorable safety profile. KT-1 is designed for an improved treatment of Acute Myeloid Leukemia by improved elimination of the relapse-inducing AML Leukemia Stem Cells (AML LSCs). KT-1 binds the clinically validated cell surface markers CD33 and CD123, which are present in greater copy numbers on AML LSCs than on bulk AML cells and corresponding normal cells, and thereby is expected to reach a preferential elimination of LSCs. PROJECT STATUS: "Clinical Candidate Selected". KT-1 is in advanced preclinical development. Excellent CMC properties and anti-leukemic efficacy. Successful 1st Scientific Advice meeting with the Paul Ehrlich Institute (PEI) in 2021. PIPELINE: Trilytes for the treatment of solid tumors (prostate cancer) planned. PATENTS: 2 Patents protecting the Trilyte technology awarded in the EU. Application for KT-1 filed in EU, US & Canada. FAU grants Kos-mas exclusive license for the IP portfolio. TEAM: Highly competent team. Clinical partners for First-In-Human (FIH) clinical trial of KT-1 identified. Draft study plan ap-proved by the PEI. FINANCE: Kosmas seeks SEED funding for the late preclinical development and a series A investment for a clinical batch of KT-1 and the FIH trial.
Daniel Norman1, Ermioni Kalfopoulou1, Simona Bianca1, Anja Leimpek1, Valeria Napolitano2,3, Mark Bostock2,3, Vadim Korotkov4, Michael Sattler2,3,5, Mark Brönstrup4,6, Gregor Popowicz2,3, Hannelore Meyer1,5
The rapid emergence of carbapenemases is a threat to the current operation of modern healthcare with widespread consequences, since infection prevention plays a crucial role for other healthcare practices e.g. surgery, immuno-affective treatments for cancer etc. These enzymes confer resistance against all types of ß-lactam antibiotics – including last-line carbapenems. As carbapenemase-positive pathogens also commonly express resistance to other classes of antibiotics, treatment options are even further limited. Novel treatment options are needed: new chemistries with new modes of action to (sustainably) overcome resistance mechanisms, in particular for Gram-negative carbapenem-resistant pathogens, assigned by WHO priority pathogens list as critical status.
We are working to develop a new class of carbapenemase inhibitors for clinical use in combination with current antibiotics, alongside its own standalone antibiotic activity in all WHO priority I pathogens. For this, we have utilised a chemistry-driven developmental process for optimising each activity of our novel fragment class: through checkerboard assays to improve metallo- and serine-based carbapenemase inhibition and through MIC screening to improve antibiotic activity in attenuated lab strains and in wild-type bacteria.
The identified fragment class (MW <300g.mol-1) shows inhibitory activity of carbapenemases and binding to the active site of metallo- and serine-carbapenemases (X-ray and NMR). We have made significant gains in biological activity to potentiate the activity of meropenem 64-fold at 16 mg/L. The fragment has clear, strong protection effects for carbapenems from a wide range of carbapenemases including metallo-based, Ambler class B, and the serine-based of class A and D. Furthermore, we have developed multiple series of compounds with antibacterial activity with MIC of 32 mg/L.
This is an invaluable starting point for an innovative antibiotic drug development. We aim to continue growing the fragment class to improve each activity. With a non-beta-lactam pharmacophore, the impact of such a molecule will be substantial for treatment of resistant infections.
Soeren Ocvirk1, Anika Sander1, Michael Blaut1
The gut microbiota has critical function for human health and recent studies demonstrated that most human disease conditions involve an altered gut microbial composition or metabolism, in particular in gastrointestinal (GI) disorders. GI health depends on balanced interactions of gut bacteria, dietary factors and the host. Shifts in these intricate relationships are linked to an increased risk for chronic GI diseases, such as colorectal cancer (CRC) or inflammatory bowel diseases (IBD). Increasing worldwide incidence of CRC or IBD, respectively, and unsolved challenges regarding precision therapies for these chronic GI diseases emphasize the need for early and targeted prevention in high-risk groups. Here, we aim to investigate factors derived from the gut microbiota (e.g., microbial metabolites) that may modulate the function of known pharmaceutical compounds as novel ‘effector molecules’ for targeted prevention of GI disorders.
By screening gut microbial co-metabolism using multi-omics methods, we identified potential synergistic tumorsuppressive and anti-inflammatory effects of specific microbial metabolites and a group of pharmaceutical compounds that act as agonist to intestine-specific host receptors. When testing combinations of these microbial metabolites and the pharmaceutical compound in a rodent CRC model, the combined administration of both molecules led to a synergistic reduction of colonic tumor numbers and intestinal inflammation (histopathological score = 1.0 ± 0.3 SEM, range: 0-6). In contrast, mice treated with microbial metabolites or the pharmaceutical compound alone did not show altered tumor formation or inflammation in the colon compared to untreated control (histopathological scores: control = 3.5 ± 0.9 SEM; microbial metabolite = 2.9 ± 0.3 SEM; pharmaceutical compound = 3.5 ± 0.4 SEM). This synergistic beneficial effect on the intestinal epithelium was confirmed by mechanistic studies using intestinal organoid cell cultures and live cell imaging.
The combination of specific microbial metabolites and pharmaceutical compounds may have significant synergistic effects in the oral chemoprevention of GI diseases, such as CRC or IBD, and warrants further analyses in the field of gut bacteria-drug interactions.
Volker Morath1, Katja Fritschle1, Markus Anneser2, Luisa Krumwiede1, Milica Zivanic1, Linda Warmuth3, Sarah Dötsch3, Stephanie Robu1, Tarik Bozoglu4, Christian Kupatt4, Markus Schwaiger1, Katja Steiger5, Dirk Busch3, Arne Skerra2, Wolfgang Weber1
Advanced medical treatments, such as cell and gene therapies, necessitate a reliable diagnostic method to image transgenes quantitatively. We developed a novel reporter gene system encoding a radiochelate-binding protein, which is suitable for both quantification of the in vivo biodistribution and proliferation of chimeric antigen receptor (CAR) T-cells and monitoring of the in vivo transduction of cells by adeno-associated viral (AAV) vectors.
The reporter protein, called DTPA-R, comprises an extracellular binding protein (Anticalin CL31d), which binds rare earth Me•DTPA complexes with sub-nanomolar affinity, the V5-tag and a membrane anchor domain. For PET imaging of this reporter protein, we have synthesized a [18F/natTb] radiohybrid ligand that can be efficiently labeled with fluorine-18, dubbed 18F-DTPA. Radiosynthesis was automated on an Eckert & Ziegler module and can be completed within 60 min.
Human T-cells were stably transduced with different versions of the reporter gene, achieving high expression levels of ~1 million receptors per cell for DTPA-R. The reporter protein did not alter the proliferation, viability, or cytotoxic effector function of T-cells, as confirmed by flow cytometry and a real time cell killing assay. The specificity of DTPA-R to the corresponding radioligand 18F-DTPA was confirmed in comparative binding studies in cell culture. PET-studies with CD1-nude mice revealed high accumulation of the radioligand in DTPA-R+ PC3 xenograft tumors with exceptional contrast and a generally low background (PC3DTPA-R-to-PC3control ratio: 43-fold at t=60 min; 23.4±2%ID/g vs. 0.5±0.06%ID/g). In AAV9 treatment studies, we could clearly detect viral transduction of even tiny anatomic structures such as adrenal glands, which correlated with immunohistochemistry. Finally, we were able to image and quantify expansion and migration of human DTPA-R+ CAR T-cells in mice bearing a CD19-positive lymphoma over a 1-month CAR-T treatment course. Bone metastases with CAR-T infiltration resulted in a maximal 18F-DTPA uptake of 23.4%ID/g in the upper body at day 14, while the control mouse only showed a maximal uptake of 1.4%ID/g.
This novel reporter gene provides a promising tool to elevate the understanding of cell and gene therapies to a new level and support the development of precision medicine. Notably, the low potential immunogenicity of the Anticalin and the usage of an already clinically used chelator paves the way for clinical translation.
Jan G. Felber*1, Lukas Zeisel*1, Annabel Kitowski1, Lena Poczka1, Karoline Scholzen2, Martin Maier1, Constanze Heise1, Julia Thorn-Seshold1, Elias S. J. Arnér2,3, Oliver Thorn-Seshold1
he cellular redox system contributes to multiple physiological processes, including ones related to the physiological energy cycle, immune processes and response mechanisms to reactive oxygen species. Dysregulations of cellular redox cascades are associated with different pathologies like cancer and inflammatory diseases, which makes involved key players valuable drug targets.[2, 3, 4] A high specificity of any diagnostic or therapeutic probe is essential to obtain information on the disease status and to enable optimal treatment efficacy. Therefore, it is our goal to develop highly selective small molecule probes that target specific enzymes within important, disease associated redox-cascades and to use them for the development of a new class of diagnostic and therapeutic relevant constructs. Focusing on the Trx/TrxR (thioredoxin/thioredoxin reductase) and GR/GSH/Grx (glutathione reductase/ glutathione/ glutaredoxin) systems, we developed a platform for the construction of either diagnostic or therapeutic proagents, consisting of di-thiol containing, enzyme selective trigger modules and variable cargo molecules. A rational design approach, considering thermodynamic and kinetic properties, as well as matching chemical properties, allowed us to develop a new class of cyclic dithiane and thiaselenane motifs that were shown to be selectively reduced by Trx or TrxR, while being stable against GSH at the same time.[5, 6] The modular synthesis approach allowed coupling of both fluorescent reporter cargos (e.g. PQ, MF) or therapeutically active moieties (e.g. SN38, CBI) and to evaluate stability, cargo release kinetics and in vitro or in vivo applicability. Constructs with fluorescent reporter cargos were studied for their enzyme selectivity in cell free and in vitro experiments and helped to understand the activation mechanism on a molecular basis. Therapeutic constructs with SN38 or the duocarmycine derivative CBI were tested in in vivo models for murine breast cancer 4T1 and humane pancreatic cancer BxPC3 for their anti-tumoral efficacy, as well as pharmacokinetic properties. To develop the platform further, additional trigger motifs selective for other enzymes in the redox cascade will be developed and will, in combination with various drug or reporter cargos, allow to construct specifically adjusted proagents for various disease settings.
Y Lan Pham1,2, Ruyi Yu1, Jonathan Beauchamp1
Non-invasive diagnostic tools based on the detection of volatile biomarkers in exhaled breath is a desirable patient-friendly alternative to blood tests . Exhaled breath is practically limitless in supply and sample analysis can be carried out directly with immediate results . However, breath-based screening approaches have largely failed to reach the necessary maturity for practical use . Despite extensive studies and reports on volatile biomarkers (or biomarker sets/patterns) relating to one disease or another, an absence of reproducibility between independent trials throws doubt on their reliability. In 2016, the International Association of Breath Research (IABR) set up a taskforce for evaluating breath sampling and analysis techniques, with accompanying benchmark data generated via the Peppermint Experiment [4, 5, 6]. The resulting data will allow researchers to evaluate and compare their methods in an evidential manner and help improve the reliability of results of breath research.
The Peppermint Experiment involves measuring the washout profiles of volatile constituents of peppermint oil in exhaled breath over time after a standardised intervention of ingesting a peppermint oil capsule. Time points are 30 min before capsule ingestion and at 60, 90, 165, 285 and 360 min post ingestion. Our approach explores the pharmacokinetics of selected terpenes using three different analytical platforms, namely comprehensive gas chromatography-mass spectrometry (GCxGC-MS), proton transfer reaction-time-of-flight-mass spectrometry (PTR-TOF-MS) and GC-ion mobility spectrometry (GC-IMS), with a focus on comparing their performances for this task.
Washout profiles from 10 participants were determined in triplicate with each of the instruments. The study aimed at estimating the range of results between the analytical platforms (inter-instrumental variations), as well as between different participants (inter-individual variations) and their repeated measurements (intra-individual variations).
This poster outlines the benchmarking concept, the methods employed, and selected results, and intends to spark debate on breath analysis in medical applications.
Sigrid Thierry 1, Andreas Hörlein1, Julia Six-Merker1,Susanne Göttlicher Vogt1, Erich Wichmann1,Thomas Hendel1, Annette Peters1
The NAKO Health Study is a large multicenter study implemented by a national network of 27 German research institutions (1) and is now open for data access applications for research purposes. Its overall aim is to provide data for the investigation of causes underlying major chronic diseases, i.e. cardiovascular diseases, cancer, diabetes, neurodegenerative/-psychiatric diseases, respiratory and infectious diseases, and their pre-clinical stages or functional health impairments.
In the baseline examination, from 2014-2019, the GNC has recruited more than 205,000 participants aged 20-69 years, drawn randomly from population registries in 18 study regions across Germany. All of them are currently being reinvited to the study centers for follow-up visits. A third examination is being planned for 2024-2028. The assessments include a face-to-face interview and touchscreen-based self-completion questionnaires, a range of medical examinations and the collection of biological material (blood, urine, saliva, nasal swabs and stool). In a randomly selected subgroup of more than 50.000 participants, an intensified examination program has been performed. In addition, in five of the 18 study centres, a total of 30,000 study participants are examined by magnetic resonance imaging (MRI) (2). Additional information is collected through a combination of active follow-up, including questionnaires every 2-3 years, and record linkage with secondary data sources, including participants health insurance records.
Helmholtz Munich is running one of NAKOs largest study centers with dedicated MRI unit and a total of 20.000 participants enrolled. Helmholtz Munich is also running the NAKOs central biorepository, where the majority of biosamples collected in the 18 study centers are stored. The highly innovative Biorepository provides very large storage capacities (> 20 mio samples) for various sample volumes to be stored at -80 or -180° C. Farmost automated sample handling for storage, selection and release allow for high throughput and high accessibility. The NAKO is planned for an overall duration of 25-30 years. It has just opened for data access applications and will provide a major resource for medical research on mechanisms, detection, prediction and primary prevention of major diseases.
Korbinian Spann1, Matthias Assenmacher2, Christian Heumann3, Michael H. Schoenberg4
Insaas.ai is a software company with a focus on data-analysis, especially colloquial patient text feedback (real world evidence). With this approach it is possible to evaluate and compare patient preference on medication and diseases for possible personalized therapies and drugs of the future.
If medication and therapies should be personalized, automation is the only way to make use of the growing amount of data. For personalized therapies and drugs, a constant feedback loop of incremental patient data is needed on top of biomarkers to provide valid insights for the healthcare industry and science.
With this challenge in mind, Insaas.ai and LMU Munich started a research project in spring 2021. Together with Prof. Christian Heumann, Matthias Assenmacher and Prof. Dr. Michael Schoenberg a first demo version was built to show the potential of this software-based research project.
For the POC, Insaas.ai crawled 30,000 entries from a public patient support group on Colon Cancer. The research question of this POC was: How relevant is Fatigue or corresponding symptoms in public patient feedback on Colon Cancer?
A set of patient texts was randomly selected and labeled by four raters manually. The outcome was a "dictionary" and a dashboard with an overview of the side effects and the tonality. Our medical advisor Prof. Michael H. Schoenberg validated the outcome.
Our poster shows this dictionary and its related terms as a cornerstone and input to train Machine Learning (AI) for further classification. In a next step this approach will be validated with University Heidelberg in an upcoming research project (beginning June 2022).
Wolfgang Sommeregger1, Katrin Illner1
Background and novelty: In biopharmaceutical processes quality is still mainly ensured using fixed process conditions following extensive product testing. The process analytical technology (PAT) initiative aims for deeper process knowledge through monitoring of critical process parameters and understanding of their influence on critical quality attributes. The latter are often evaluated after the completed process due to the bottleneck represented by the lack of data accessible in real time. In addition, data management often meets stringent regulatory requirements. Our software platform covers standardized data management, contextualization and provides a PAT based solution to monitor and perform real-time calculations based on online, at-line and offline process data. Furthermore, mathematical models provide immediate deeper process insights and can be designed to automatically predict, control, and stir the process in the desired direction.
Experimental approach: The basis of our software is the plug and play connection of all bioprocess entities in R&D and/or GMP production facilities. Our vendor independent and communication interface unrestricted approach enables data processing and management over multiple standalone devices. This allows e.g., for fully integrated cell culture perfusion processes. The process setup combines a wide variety of different equipment, i.e., pumps, scales, cell retention system, analyzers and bioreactors, from several manufacturers with a multitude of interfaces. In addition, a control strategy for a flexible perfusion rate based on real time soft sensors was implemented. The immediate advantage of accessing interlinked online and offline measurements is highlighted by the user defined visualization and control of key process indicators.
Results and discussion: The different communication interfaces in bioprocessing industries show the need of a supplier independent system to connect all devices and isolated data silos. With our software solution it is possible to move from a semi-automated to a fully automated perfusion process by utilizing an automatic cross-device control strategy which has not been possible before. Moreover, the software enables the flexible definition and monitoring of critical process parameters and gives valuable insight into process data in a simple and intuitive way. The generated process insight can further be used to develop mathematical models and extended process control strategies.
Hans-Juergen Thiesen2,3, Felix Steinbeck2,3, Michael Glockerl1
With the event of the SARS-CoV2 pandemic in March 2020, it became evident that people at elderly homes will run the highest risk to suffer from Covid-19 disease. In particular, in the early days the usage of non-pharmaceutical-interventions (NPI) had been the measure of choice. Initially, most of the deaths due to corona infections occured in the population above 65-year-old, primarily in individuals with high body mass index with manifested comorbidities such as diabetes mellitus or hypertension. However, the analysis of corona infection and death rates broken down to cohorts of 10 year-segments of age indicates that hardly 20% of elderly individuals at ages from 80 to 89 died from corona. Interestingly, computational calculations predicted, published on December 15th, 2021, that omicron infections should lead to reduced lethalities (Ref. 1). Lethality rates from January 2022 collected by the Robert-Koch-Institute (RKI) revealed an about ten fold drop in lethality rates (Ref. 2). Our studies indicate that the percentage of deaths do not show a dramatic difference in the age groups between 2020 (nonvaccinated) and 2021 (vaccinated individuals), but a big difference is visible between infections with delta and omicron (Ref. 3). From the beginning, we assumed that differences in death rates within age groups will not just be due to individual immune status but be based on combinatory individual genetic single nucleotides (SNPs). Our data analyses indicate: The best individual protection besides NPI and reduced contacts will be in autumn 2022 to determine individual immunity parameters, such as antibody levels against SARS-CoV2 spike as well as N-capsid proteins in regard to age, BMI, comordidities and age. In ongoing studies, we favour the comparative analyses using completely sequenced genomes derived from elderly that hardly showed any symptoms while having stayed in elderly homes in 2020 plus having been in closed contact with healthy elderly that died from covid-19 infection. Supported by own data analysis, we foresee, in the near future the group of high vulnerables might stratified by making use of DTC genetic testing to assess their individual genetic risk in combination with BMI, age, medical history, life style and timely determined corona antibody titres. We like to encourage policy maker and medical societies to encourage vulnerables to get assessed their own covid-19 risk (one of the issues in P4 Medicine, the participartory component).
Maria Stecklum1, Annika Wulf-Goldenberg1, Bernadette Brzezicha1, Wolfgang Walther1,2, Christian Rupp1, Jens Hoffmann1
Background: The preclinical evaluation of novel immune therapies demands humanized mouse models with functional human immune cells. In previous studies we have demonstrated, that either peripheral blood mononuclear cells (PBMCs) or subpopulations of PBMCs like T- and NK-cells or hematopoietic stem cells (HSC) can be used to establish a humanized immune system with functional T-, B-, and NK cells, as well as monocytes and dendritic cells in immunodeficient mice. By transplantation of cell-line-derived (CDX) or patient-derived (PDX) tumor xenografts on humanized mice, we successfully generated a full human tumor-immune-cell model for different tumor entities. Finally, we validated the functionality of these models using checkpoint inhibitors like Ipilimumab (Ipi), Nivolumab (Nivo), Pembrolizumab (Pembro), cell therapies and immune cell engagers.
Methods: HSC-humanized mice were generated by i.v. transplantation of CD34+stem cells to immunodeficient NOG mice. PBMC or isolated T- or NK-cell preparations were used to humanize mice by single or multiple i.v. injections. CDX and PDX from different entities (i.e. lymphoma, neuroblastoma, and breast cancer) were transplanted on those humanized mice. These models were used to evaluate novel immune therapies. Blood and tumor samples were analyzed by FACS for immune cell infiltration and activation.
Results: The transplanted HSCs engrafted in mice and established a functional human immune system with proliferation and differentiation. 14 weeks after HSC inoculation up to 20% of the human immune cells in the blood were functional T-cells, characterized by a high PD-1 expression. The selected CDX and PDX tumors successfully engrafted on humanized mice without significant differences in tumor growth compared to non-humanized mice. Checkpoint inhibitor treatments induced tumor growth delay in selected models. FACS analysis of tumors revealed an increased percentage of tumor infiltrating T-cells. We identified a set of CDX and PDX models without interference with parallel injection of PBMC, T- or NK-cell preparations for the evaluation of immune cell engagers and other cell therapies.
Conclusions: We established human tumor-immune-cell models of different entities using CDX or PDX in combination with different donor derived immune cell subsets as effector cells. We demonstrated successful engraftment of HSC on immunodeficient mouse strains, generating mice with a functional human hematopoiesis. These models have been employed for preclinical evaluation of novel checkpoint inhibitors, cell therapies and immune cell engagers. Our models allow preclinical, translational studies on tumor immune biology as well as evaluation of new therapies, drug combinations and biomarker identification and validation.