American Association for Cancer Research
Browse

sorry, we can't preview this file

cir-21-0594_supplementary_data_suppsf1-sf10_sv1-sv4.docx (5.44 MB)

Supplementary Data from Visualizing Spatial and Stoichiometric Barriers to Bispecific T-Cell Engager Efficacy

Download (5.44 MB)
journal contribution
posted on 2023-04-04, 01:24 authored by Ran You, Jordan Artichoker, Arja Ray, Hugo Gonzalez Velozo, Dan A. Rock, Kip P. Conner, Matthew F. Krummel
Supplementary Data from Visualizing Spatial and Stoichiometric Barriers to Bispecific T-Cell Engager Efficacy

Funding

RRID

NIH

Cancer Research Institute

History

ARTICLE ABSTRACT

Bispecific T-cell engager (BiTE) molecules are biologic T cell–directing immunotherapies. Blinatumomab is approved for treatment of B-cell malignancies, but BiTE molecule development in solid tumors has been more challenging. Here, we employed intravital imaging to characterize exposure and pharmacodynamic response of an anti-muCD3/anti-huEGFRvIII mouse surrogate BiTE molecule in EGFR variant III (EGFRvIII)-positive breast tumors implanted within immunocompetent mice. Our study revealed heterogeneous temporal and spatial dynamics of BiTE molecule extravasation into solid tumors, highlighting physical barriers to BiTE molecule function. We also discovered that high, homogeneous EGFRvIII expression on cancer cells was necessary for a BiTE molecule to efficiently clear tumors. In addition, we found that resident tumor-infiltrating lymphocytes (TIL) were sufficient for optimal tumor killing only at high BiTE molecule dosage, whereas inclusion of peripheral T-cell recruitment was synergistic at moderate to low dosages. We report that deletion of stimulatory conventional type I DCs (cDC1) diminished BiTE molecule–induced T-cell activation and tumor clearance, suggesting that in situ antigen-presenting cell (APC) engagements modulate the extent of BiTE molecule efficacy. In summary, our work identified multiple requirements for optimal BiTE molecule efficacy in solid tumors, providing insights that could be harnessed for solid cancer immunotherapy development.

Usage metrics

    Cancer Immunology Research

    Categories

    Keywords

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC