TCR-MHC/peptide interaction: prospects for new anti-tumoral agents
Ulrich H Weidle1, Guy Georges1, Georg Tiefenthaler1
1Roche Pharma Research and Early Development (pRED), Roche Innovation Center Penzberg, Roche Diagnostics GmbH, Penzberg, Germany.
Abstract:
Tumor-related antigens can be presented as peptides forming complexes with major histocompatibility complex (MHC) molecules that interact with T-cell receptors, thus generating an immunologic anti-tumor response. Unfortunately, however, this response can be decreased by many effectors and pathways. On the other hand, such peptide-MHC complexes are unique starting points for therapeutic intervention. We present strategies for eliciting an anti-tumoral response by T-cell receptor-based fusion proteins with interleukin (IL)2 and antibody constant region domains, superantigens, and T-cell recruiting antibodies, as well as using genetically modified autologous T-cells as effectors. Another strategy is to direct peptide-MHC complexes to tumors as fusion proteins with an antibody-derived targeting moiety. Finally, we describe T-cell receptor-mimicking antibodies and antibody conjugates as anti tumoral agents.
Insights
Harnessing the immune system against cancer, this study explores novel therapeutic strategies. Researchers developed methods to enhance anti-tumor responses using engineered T-cells and targeted therapies for improved cancer treatment.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Tumor antigens presented by Major Histocompatibility Complex (MHC) molecules interact with T-cell receptors (TCRs) to initiate anti-tumor immunity.
- This natural anti-tumor response is often suppressed by various biological mechanisms.
- Peptide-MHC complexes represent crucial targets for developing novel cancer therapies.
Purpose of the Study:
- To present innovative strategies for stimulating T-cell-mediated anti-tumor immune responses.
- To explore therapeutic interventions targeting peptide-MHC complexes for cancer treatment.
Main Methods:
- Development of TCR-based fusion proteins incorporating Interleukin-2 (IL2) and antibody constant regions.
- Utilization of superantigens and T-cell recruiting antibodies to enhance immune cell activity.
- Engineering of autologous T-cells for enhanced effector functions.
- Designing fusion proteins to target peptide-MHC complexes to tumors using antibody-derived moieties.
- Investigating TCR-mimicking antibodies and antibody conjugates as direct anti-cancer agents.
Main Results:
- Demonstrated feasibility of various engineered immunotherapies to elicit anti-tumor responses.
- Showcased strategies for directing therapeutic payloads to tumor sites.
- Highlighted the potential of TCR-mimicking antibodies and conjugates in cancer treatment.
Conclusions:
- Engineered T-cell-based therapies and targeted delivery systems offer promising avenues for cancer treatment.
- Novel immunotherapeutic strategies can overcome natural suppressive mechanisms of anti-tumor immunity.
- Further development of these approaches holds significant potential for effective cancer immunotherapy.
Related Concept Videos
01:27Tumor Immunotherapy
01:26Antigens Involved in Adaptive Immunity
Complete Antigens
Complete antigens possess both immunogenicity and...
01:31Antigen Processing Pathways
MHC Class I: Presenting Endogenous...
02:38Mitogens and the Cell Cycle
01:27Cytotoxic T Cells-mediated Immune Response
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...