Visualizing Spatial and Stoichiometric Barriers to Bispecific T-Cell Engager Efficacy
- 12 April 2022
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Immunology Research
- Vol. 10 (6), 698-712
- https://doi.org/10.1158/2326-6066.cir-21-0594
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.Keywords
Other Versions
Funding Information
- RRID (SCR_018206)
- NIH (P30DK063720)
- NIH (R01AI052116)
- Cancer Research Institute (CRI2940)
This publication has 56 references indexed in Scilit:
- Critical Roles of a Dendritic Cell Subset Expressing a Chemokine Receptor, XCR1The Journal of Immunology, 2013
- Regression of Human Prostate Cancer Xenografts in Mice by AMG 212/BAY2010112, a Novel PSMA/CD3-Bispecific BiTE Antibody Cross-Reactive with Non-Human Primate AntigensMolecular Cancer Therapeutics, 2012
- Sphingosine-1-Phosphate and Lymphocyte Egress from Lymphoid OrgansAnnual Review of Immunology, 2012
- T Cell Receptors are Structures Capable of Initiating Signaling in the Absence of Large Conformational RearrangementsOnline Journal of Public Health Informatics, 2012
- Marginating Dendritic Cells of the Tumor Microenvironment Cross-Present Tumor Antigens and Stably Engage Tumor-Specific T CellsCancer Cell, 2012
- Immunomodulatory therapy of cancer with T cell-engaging BiTE antibody blinatumomabExperimental Cell Research, 2011
- T cell-engaging BiTE antibodies specific for EGFR potently eliminate KRAS- and BRAF-mutated colorectal cancer cellsProceedings of the National Academy of Sciences of the United States of America, 2010
- Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8α+ conventional dendritic cellsThe Journal of Experimental Medicine, 2010
- Tyrosine kinase receptor RET is a key regulator of Peyer’s Patch organogenesisNature, 2007
- A rat antibody against a structure functionally related to the mouse T-cell receptor/T3 complexImmunogenetics, 1988