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The Intracellular Proteome as a Source for Novel Targets in CAR-T and T-Cell Engagers-Based Immunotherapy
Inbar Arman1, Maya Haus-Cohen1, Yoram Reiter1
1Laboratory of Molecular Immunology and Immunotherapy, Faculty of Biology, Technion-Israel Institute of Haifa, Haifa 320003, Israel.
Abstract:
The impressive clinical success of cancer immunotherapy has motivated the continued search for new targets that may serve to guide potent effector functions in an attempt to efficiently kill malignant cells. The intracellular proteome is an interesting source for such new targets, such as neo-antigens and others, with growing interest in their application for cell-based immunotherapies. These intracellular-derived targets are peptides presented by MHC class I molecules on the cell surface of malignant cells. These disease-specific class I HLA-peptide complexes can be targeted by specific TCRs or by antibodies that mimic TCR-specificity, termed TCR-like (TCRL) antibodies. Adoptive cell transfer of TCR engineered T cells and T-cell-receptor-like based CAR-T cells, targeted against a peptide-MHC of interest, are currently tested as cancer therapeutic agents in pre-clinical and clinical trials, along with soluble TCR- and TCRL-based agents, such as immunotoxins and bi-specific T cell engagers. Targeting the intracellular proteome using TCRL- and TCR-based molecules shows promising results in cancer immunotherapy, as exemplified by the success of the anti-gp100/HLA-A2 TCR-based T cell engager, recently approved by the FDA for the treatment of unresectable or metastatic uveal melanoma. This review is focused on the selection and isolation processes of TCR- and TCRL-based targeting moieties, with a spotlight on pre-clinical and clinical studies, examining peptide-MHC targeting agents in cancer immunotherapy.
Insights
Cancer immunotherapy is advancing by targeting intracellular proteins presented on MHC class I molecules. T-cell receptor (TCR)-like (TCRL) and TCR-based therapies show promise for killing cancer cells.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Cancer immunotherapy has seen significant clinical success, driving the search for novel therapeutic targets.
- The intracellular proteome is a promising source for new cancer targets, including neoantigens.
- Intracellular targets are presented as peptides on MHC class I molecules, making them accessible for immune recognition.
Purpose of the Study:
- To review the selection and isolation processes for TCR- and TCRL-based targeting moieties.
- To highlight pre-clinical and clinical studies investigating peptide-MHC targeting agents in cancer immunotherapy.
- To discuss the potential of targeting the intracellular proteome for enhanced cancer treatment.
Main Methods:
- Focus on the selection and isolation strategies for TCR- and TCRL-based targeting moieties.
- Analysis of pre-clinical and clinical studies involving peptide-MHC targeting agents.
- Examination of therapeutic approaches utilizing T-cell receptor (TCR) engineered cells and TCR-like (TCRL) antibodies.
Main Results:
- TCR- and TCRL-based molecules targeting the intracellular proteome demonstrate promising results in cancer immunotherapy.
- The anti-gp100/HLA-A2 TCR-based T cell engager is an example of successful FDA-approved therapy for uveal melanoma.
- Adoptive cell transfer and soluble agents targeting peptide-MHC complexes are under investigation in clinical trials.
Conclusions:
- Targeting intracellular peptides presented by MHC class I molecules is a viable strategy in cancer immunotherapy.
- TCR- and TCRL-based agents offer potent effector functions for killing malignant cells.
- Continued research into selection and isolation methods will advance the development of these targeted therapies.
