2018 MI Bioresearch Mid-Year Review

June 19, 2018

MI Bioresearch has started off 2018 with exciting advances in our available tumor models and capabilities to support your traditional oncology and immuno-oncology research. We have kept pace with the expanding scope of immuno-oncology research by deeper exploration of new models and novel methods to enhance our offerings to our clients. We are continuously expanding our capabilities to meet with emerging clinical combinations in the immuno-oncology space including focal beam radiation combinations in syngeneic models to support preclinical testing. In both the immuno-oncology and traditional oncology space, continual investment in orthotopic and metastatic models has allowed us to broaden our imaging and surgical capabilities to meet and surpass client expectations.

In line with our commitment to offer the best guidance to our clients, our February 2018 blog provided in-depth insight into strategies for selecting an optimal immuno-oncology tumor model. This blog offers clients an invaluable understanding of features such as tumor placements, immune composition, and response to treatments to help guide the design of an effective study. The blog illustrates many of the key aspects we’ve been focusing on this year including immunophenotyping, drug combinations and the effect of immune priming by radiation.

 

Tumor Models

We have continued our internal investment in the development and optimization of syngeneic models. Over the last six months we have optimized the growth parameters for Hepa 1-6, EMT-6, E0771, and ID8.

MI Bioresearch also sees great value in our more than 200 human xenograft lines; understanding their unique mutations is key in guiding our clients to the right models. We presented two model spotlights (Part 1 and Part 2) exploring our most widely used human lung models.

New Models:

The mouse Hepa 1-6 line was derived from a spontaneously arising hepatoma in the C57L strain. We have determined the optimal implant conditions for Hepa 1-6 as a subcutaneous model in its syngeneic C57L/J strain and in the histocompatible C57BL/6 strain. From our initial pilot growth kinetics studies shown below, the model grows well in both strains with similar kinetics. Efficacy studies with checkpoint inhibitors are in progress.

Hepa 1-6 - Hepatoma Syngeneic Model.

New Model Spotlights:

  • Murine EMT6 and E0771 Breast Cancer Models have been recently validated as orthotopic triple negative breast cancer (TNBC) models. These models have been well characterized for in vivo growth parameters, response to immuno-oncology agents, and in combination with radiation. Tumor immune profiles are available for both models.
    EMT6    E0771

Model Optimization Spotlights:

  • Murine ID8-Luc-mCh-Puro Ovarian Cancer has been optimized as a luciferase-enabled orthotopic model (intra-peritoneal implant) for in vivo testing with bioluminescence imaging to track disease burden. Based on initial in vivo BLI data, ID8 is highly sensitive to immune checkpoint inhibitors (anti-mPD-1 and anti-mPD-L1). Optimization for combination therapy is in progress.
    ID8
  • The highlight of our Feb and March spotlight was a comprehensive synopsis of several of our human Non-Small-Cell Lung Carcinoma (NCSLC) cell lines. In vivo growth kinetics for subcutaneous, intracranial (pseudo metastatic disease) and orthotopic have been characterized and are available. For both the intracranial and orthotopic implant methods disease progression is monitored by either MRI or bioluminescence imaging.
    NSCLC – Part 1    NSCLC – Part 2

 

Radiation Therapy

Radiotherapy is a cornerstone treatment for cancer patients. Clinically, radiation combinations with immunotherapies are being evaluated based on preclinical data suggesting additive or synergistic activities. Radiation therapy (RT) can induce a shift to a pro-inflammatory phenotype in the tumor microenvironment which can result in the activation of an anti-tumor immune response that enhances the effects of radiotherapy. However, RT alone can be insufficient to induce a curative anti-tumor immune response especially against metastatic cancer, highlighting the need for combination immunotherapy strategies to boost the immune system. Using the Small Animal Radiation Research Platform (SARRP) by Xstrahl, we are actively pursuing RT combination therapies and some of those results were showcased in the following posters presented during the American Association of Cancer Researchers (AACR) 2018 Annual Meeting.

  • Radiation Enhances Anti-Tumor Activity of Checkpoint Blockade in Syngeneic Tumor Models – This poster is a comprehensive review of RT combinations with checkpoint inhibitors in breast, colon, B-Cell lymphoma, and glioblastoma models. It illustrates the use of tools such as SARRP to enhance the ability of preclinical models to provide a first line assessment for advanced I/O therapy combinations.
    I/O-Radiotherapy Combination
  • A Comparative Evaluation of Immunotherapy Responses in Murine Colon Carcinoma – This poster highlights the efficacy evaluation of anti-PD-1 checkpoint inhibitor combinations in the CT26 model with an IDO1 inhibitor, focal radiation and 5-FU. Further it also evaluates the response of CT26 to costimulatory agents.
    CT26 Combination

 

Advances in Methods for Immuno-Oncology Research

The ability to monitor tumor infiltrating immune cell changes in response to therapy, pharmacodynamic immune profiling, is invaluable when attempting to elucidate the cellular mechanism of action of an immunotherapy. MI Bioresearch has continued to invest heavily in new tools and methods for assessment of immune cells and their function in tumors and secondary lymphoid organs. Our flow cytometry core has refined the markers in our MI-CompT and MI-TAM panels such that they now provide greater mechanistic information to clients. Further, we have developed more specialized functional T cell panels to support assessment of novel agents. As a complementary technology to flow cytometry that can provide valuable spatial information on the immune cells in a tumor, MI Bioresearch has expanded our immunohistochemistry (IHC) and immunofluorescence (IF) capabilities.

  • Phospho-Protein Detection in Solid Tumors Using Phospho-Flow Cytometry was our technology spotlight highlighting advances in the detection of protein phosphorylation by flow cytometry in ex vivo dissociated tumor samples from mice treated with a test agent.
    Phospho-Protein Detection (Tech Spotlight)
  • Phospho-Protein Detection in Solid Tumors Using Phospho-Flow Cytometry was our poster presented at AACR 2018 that described more complex phospho-flow cytometry on syngeneic tumors ex vivo.  MAP-kinase phospho-protein phosphorylation was assessed in the tumor cells while simultaneously phospho-STAT proteins were analyzed in tumor infiltrating immune cells.  This allow simultaneous assessment of tumor cell and immune cell signaling.
    Phospho-Protein Detection (Poster)
  • Flow Cytometry-Based Tools to Enrich Your Preclinical Immuno-Oncology Research was our webinar in May that provided an overview of new markers for elucidation of activated T cells in our MI-CompT panel and markers for dendritic cell analysis in our MI-TAM panel. The use of intracellular cytokine detection for assessment of tumor infiltrating T cell function was also described.  Finally, we presented more in-depth information on the development of panels for simultaneous tumor cell and immune cell phospho-protein detection.
    Flow Cytometry-Based Tools
  • Multiplex IHC for Patterns of Protein Expression, Co-expression, and Spatial Relationships was our technology spotlight that highlighted our multiplex immune cell detection panels. These IHC panels can be used to assess the impact of an immunotherapy on the numbers and spatial organization of various immune cell populations in a tumor.
    Multiplex IHC

Up and Coming in 2018

In the next half of 2018, we will bring you new Model Spotlights including efficacy data in our Hepa 1-6 hepatoma model and refinements to dosing of checkpoint inhibitors in the ID8-Luc-mCh-Puro ovarian cancer model. On the topic of focal radiation, we will have new data with immuno-therapy/radiotherapy combinations in the syngeneic A20 B cell lymphoma model and the 4T1 breast carcinoma model. Our Blogs and Technology Spotlights will continue to highlight our ongoing investment in research and development. For more information on any of these topics, or other topics from our website, please communicate with our scientists or visit our Knowledge Center.