Mechanistic insights into resistance mechanisms to T cell engagers
Linlin Cao1, Gabrielle Leclercq-Cohen1, Christian Klein2
1Roche Innovation Center, Zürich, Switzerland.
Abstract:
T cell engagers (TCEs) represent a groundbreaking advancement in the treatment of B and plasma cell malignancies and are emerging as a promising therapeutic approach for the treatment of solid tumors. These molecules harness T cells to bind to and eliminate cancer cells, effectively bypassing the need for antigen-specific T cell recognition. Despite their established clinical efficacy, a subset of patients is either refractory to TCE treatment (e.g. primary resistance) or develops resistance during the course of TCE therapy (e.g. acquired or treatment-induced resistance). In this review we comprehensively describe the resistance mechanisms to TCEs, occurring in both preclinical models and clinical trials with a particular emphasis on cellular and molecular pathways underlying the resistance process. We classify these mechanisms into tumor intrinsic and tumor extrinsic ones. Tumor intrinsic mechanisms encompass changes within tumor cells that impact the T cell-mediated cytotoxicity, including tumor antigen loss, the expression of immune checkpoint inhibitory ligands and intracellular pathways that render tumor cells resistant to killing. Tumor extrinsic mechanisms involve factors external to tumor cells, including the presence of an immunosuppressive tumor microenvironment (TME) and reduced T cell functionality. We further propose actionable strategies to overcome resistance offering potential avenues for enhancing TCE efficacy in the clinic.
Insights
T cell engagers (TCEs) show promise for treating cancers by directing T cells to kill tumor cells. This review details resistance mechanisms and strategies to improve TCE therapy effectiveness.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- T cell engagers (TCEs) are effective in treating B cell malignancies and solid tumors by redirecting T cells to eliminate cancer cells.
- Despite clinical success, patient resistance to TCE therapy, both primary and acquired, limits treatment efficacy.
- Understanding resistance mechanisms is crucial for optimizing TCE-based cancer treatments.
Purpose of the Study:
- To comprehensively review resistance mechanisms to TCEs in preclinical models and clinical trials.
- To classify resistance into tumor-intrinsic and tumor-extrinsic categories.
- To propose strategies for overcoming TCE resistance and enhancing clinical efficacy.
Main Methods:
- Literature review of preclinical models and clinical trials on TCE resistance.
- Classification of resistance mechanisms into tumor-intrinsic and tumor-extrinsic factors.
- Analysis of cellular and molecular pathways underlying TCE resistance.
Main Results:
- Tumor-intrinsic resistance mechanisms include antigen loss and expression of immune checkpoint ligands.
- Tumor-extrinsic resistance mechanisms involve an immunosuppressive tumor microenvironment and impaired T cell function.
- Both mechanisms contribute to reduced T cell-mediated cytotoxicity against cancer cells.
Conclusions:
- Resistance to TCEs is multifactorial, involving both tumor cell-autonomous and microenvironment-dependent factors.
- Identifying and targeting these resistance mechanisms can improve patient outcomes.
- Developing strategies to overcome resistance is key to unlocking the full potential of TCEs in cancer therapy.
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