Request CrownBio Posters from CRI-CIMT-EATI-AACR
Use the form to request copies of our posters presented at the 2nd CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference held in New York City, US.
A140 Checkpoint Inhibitor Modulation of Tumor Microenvironment at Orthotopic and Metastatic Sites Using Bioluminescent Syngeneic Cell Line Models in Immune Competent Mice.
Andrew McKenzie1, Nektaria Papadopoulou1, Simon Jiang1, Jane Wrigley1, Kelly Jones1, Russell Garland2, Neil Williams2, Rajendra Kumari1
1Crown Bioscience UK, Loughborough, United Kingdom; 2KWS Biotest, Bristol, United Kingdom.
Syngeneic models are widely used to model the impact of cancer immunotherapy on tumor growth and tumor invading leucocytes (TILs), and the majority of such work is typically carried out in the subcutaneous setting. However, orthotopic models are known to better model cancer in patients as they form a single focal disease area as in the patient situation, facilitate metastatic spread via intra- and extra-thoracic lymph nodes and, in the case of syngeneic models, strain-specific tumor microenvironment interactions (immune and stromal components). Bioluminescent imaging (BLI) increases the usefulness of such models, as it allows for non-invasive longitudinal monitoring of tumor burden, allowing for optimal randomization and reduction of false positives. It also allows continuous feedback allowing one to optimize treatment regimen mid-study. Herein we describe the generation of several bioluminescent variants of syngeneic cell lines commonly used for immunotherapy studies and assess the impact of orthotopic growth on response to immune checkpoint therapy.
B098 MuScreen™: In Vivo Screening On A Panel of Well-Characterized Syngeneic Models.
Ying Jin, Lan Zhang, Juan Zhang, Eric Murphy, Zhongliang Li, Meng Qiao, Qian Shi.
Crown Bioscience, Taicang, China.
Background: Syngeneic tumor models have proven to be one of the most robust model systems for cancer immunotherapy. In vitro screens frequently used in oncology to quickly identify cells, models, and PD effects for further study often fail in immuno-oncology, due to immunotherapeutics targeting the complex host immune system. Alternatively, an in vivo screen with a panel of models addresses many of these questions, e.g. PD and efficacy, but may be cost prohibitive.
Material and methods: Leveraging in-house detailed profiling data on our syngeneic models, including efficacy benchmarking with aPD-1, aPD-L1 and aCTLA-4 antibodies, RNAseq data on tumor samples, and FACS analysis on both baseline and treatment response tumor samples, CrownBio recently launched a new service platform: MuScreen. MuScreen includes up to 20 well-characterized syngeneic models in a 3 month screening run. Both PD and efficacy may be determined in the run, allowing researchers to make decisions based on results observed from a large dataset. To address cost issues, test agents from multiple clients are pooled together for each run (sharing vehicle and other common groups) providing a significant reduction in the number of animals used and the associated costs.
Results: CrownBio has established the largest collection of syngeneic models with well-characterized immunotherapy data. In the first MuScreen run, we have generated new data on common IO agents, e.g. aPD-1 antibody, with FACS analysis, IHC, and efficacy data. The first set of MuScreen data is shown.
Conclusions: MuScreen is the first in vivo screening tool for cancer immunotherapeutics. It provides detailed response data on a panel of syngeneic models, therefore enabling better decision making in a cost and time efficient manner.
B137 Establishment of a Variety of Primary Mouse Tumor Allografts of Defined Disease Pathways for Evaluating Immunotherapy.
Jiagui Qu, Davy Ouyang, Annie An, Henry Li.
Crown Bioscience Inc., Santa Clara, CA.
The lack of relevant animal models is a major bottleneck for developing novel immunotherapies. Syngeneic mouse tumor models, where mouse cancer cell lines were engrafted in mice from the same strain, are the current workhorse. However, these models suffer from several limitations: 1) only a limited number of models are available and responsive to current checkpoint inhibitors; thus for each given strain of mouse, there is little choice of cells/disease types; 2) models don’t mimic patient tumors since they are derived from in vitro immortalized cell lines; 3) they are not reflective of patient disease pathways thus unfit for common targeted agents, in mono- or combination therapy. We have established allografts of spontaneous mouse tumors (MuPrime™) derived from genetically engineered mouse models (GEMMs) as a new type of immuno-oncology model with the following advantages: 1) MuPrime conserve the primary nature of “stem cell diseases” and relevant tumor microenvironment as seen in patients and patient-derived xenografts (PDX); 2) MuPrime is a diverse collection of cancer types/strains of mice; 3) MuPrime models carry engineered oncogenic drivers which recapitulate the human diseases, e.g. APCMin mutation, KRAS mutation, P53 loss-of-function, etc., deriving from a wide range of available GEMMs, suitable for targeted agents. Thus far, we have built a small library of allografts and are testing them to facilitate pharmacological investigation, particularly for immuno-oncology agents.
KRAS G12D mutation and P53 loss-of-function are the most common genetic abnormality found in a variety of cancers, e.g. lung, pancreas, colon, lymphoma, etc. We generated a conditional compound mutant GEMM. By introducing adeno-Cre to different organ sites of this GEMM, we created a series of mouse tumors, including lung, pancreas, colon, and lymphoma, with genetic lesions bearing KRASG12D/+/P53-/-. MuPrime allografts were established by engraftment of these primary tumors to the C57BL/6 syngeneic host. These allograft tumors, while carrying the same mutations, display distinct histopathology: pancreatic tumors exhibit the features commonly found in human PDAC (e.g. glandular tumor structures and exuberant stroma); lung cancer features NSCLC-adenocarcinoma. They also display different tumor immune microenvironments. This set of allografts of different diseases, but with the same oncogenic driver, are ideal models to investigate sensitivity to immunotherapies, as well as to combination therapies targeting MAPK pathway and immune modulation, across a range of tumor types.