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Updated: Jun 23, 2026
Generation of Orthotopic Pancreatic Tumors and Ex vivo Characterization of Tumor-Infiltrating T Cell Cytotoxicity
Published on: December 7, 2019
Predicting Tumor Killing and T-Cell Activation by T-Cell Bispecific Antibodies as a Function of Target Expression:
Arthur J Van De Vyver1,2, Tina Weinzierl3, Miro J Eigenmann4
1Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, Switzerland. arthur.van_de_vyver@roche.com.
Abstract:
Targeted T-cell redirection is a promising field in cancer immunotherapy. T-cell bispecific antibodies (TCB) are novel antibody constructs capable of binding simultaneously to T cells and tumor cells, allowing cross-linking and the formation of immunologic synapses. This in turn results in T-cell activation, expansion, and tumor killing. TCB activity depends on system-related properties such as tumor target antigen expression as well as antibody properties such as binding affinities to target and T cells. Here, we developed a systems model integrating in vitro data to elucidate further the mechanism of action and to quantify the cytotoxic effects as the relationship between targeted antigen expression and corresponding TCB activity. In the proposed model, we capture relevant processes, linking immune synapse formation to T-cell activation, expansion, and tumor killing for TCBs in vitro to differentiate the effect between tumor cells expressing high or low levels of the tumor antigen. We used cibisatamab, a TCB binding to carcinoembryonic antigen (CEA), to target different tumor cell lines with high and low CEA expression in vitro We developed a model to capture and predict our observations, as a learn-and-confirm cycle. Although full tumor killing and substantial T-cell activation was observed in high expressing tumor cells, the model correctly predicted partial tumor killing and minimal T-cell activation in low expressing tumor cells when exposed to cibisatamab. Furthermore, the model successfully predicted cytotoxicity across a wide range of tumor cell lines, spanning from very low to high CEA expression.
Insights
T-cell bispecific antibodies (TCB) show promise in cancer immunotherapy by redirecting T-cells to kill tumor cells. A new model accurately predicts TCB efficacy based on tumor antigen expression levels.
Area of Science:
- Immunology
- Oncology
- Systems Biology
Background:
- T-cell bispecific antibodies (TCB) represent a novel approach in cancer immunotherapy.
- TCBs facilitate T-cell and tumor cell binding, forming immunologic synapses to activate T-cells and induce tumor cell killing.
- TCB efficacy is influenced by factors like tumor antigen expression and antibody binding affinities.
Purpose of the Study:
- To develop a systems model integrating in vitro data to understand TCB mechanisms of action.
- To quantify the relationship between tumor antigen expression and TCB-mediated cytotoxic effects.
- To differentiate TCB activity in tumor cells with varying target antigen expression levels.
Main Methods:
- Development of a systems model to capture TCB-related processes, including immune synapse formation, T-cell activation, expansion, and tumor killing.
- Utilizing cibisatamab, a TCB targeting carcinoembryonic antigen (CEA), to test against tumor cell lines with differential CEA expression in vitro.
- Employing a learn-and-confirm cycle to refine the model based on experimental observations.
Main Results:
- The model accurately predicted substantial T-cell activation and complete tumor killing in high CEA-expressing tumor cells treated with cibisatamab.
- The model correctly predicted minimal T-cell activation and partial tumor killing in low CEA-expressing tumor cells.
- The model demonstrated successful prediction of cytotoxicity across a broad spectrum of CEA expression levels.
Conclusions:
- The developed systems model effectively elucidates TCB mechanisms and quantifies their cytotoxic effects.
- Tumor target antigen expression is a critical determinant of TCB efficacy.
- This modeling approach can predict TCB performance in various tumor contexts, aiding in therapeutic development.
