Host Interactions with Engineered T-cell Micropharmacies
Related Experiment Video
Updated: Jul 25, 2025
Non-Viral Engineering of Primary Human T Cells via Homology-Mediated End-Joining Targeted Integration of Large DNA Templates
Published on: May 9, 2025
Christopher M Bourne1,2, Patrick Wallisch2,3, Megan M Dacek2,3
1Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York.
Abstract:
Genetically engineered, cytotoxic, adoptively transferred T cells localize to antigen-positive cancer cells inside patients, but tumor heterogeneity and multiple immune escape mechanisms have prevented the eradication of most solid tumor types. More effective, multifunctional engineered T cells are in development to overcome the barriers to the treatment of solid tumors, but the interactions of these highly modified cells with the host are poorly understood. We previously engineered prodrug-activating enzymatic functions into chimeric antigen receptor (CAR) T cells, endowing them with a killing mechanism orthogonal to conventional T-cell cytotoxicity. These drug-delivering cells, termed Synthetic Enzyme-Armed KillER (SEAKER) cells, demonstrated efficacy in mouse lymphoma xenograft models. However, the interactions of an immunocompromised xenograft with such complex engineered T cells are distinct from those in an immunocompetent host, precluding an understanding of how these physiologic processes may affect the therapy. Herein, we expanded the repertoire of SEAKER cells to target solid-tumor melanomas in syngeneic mouse models using specific targeting with T-cell receptor (TCR)-engineered T cells. We demonstrate that SEAKER cells localized specifically to tumors, and activated bioactive prodrugs, despite host immune responses. We additionally show that TCR-engineered SEAKER cells were efficacious in immunocompetent hosts, demonstrating that the SEAKER platform is applicable to many adoptive cell therapies.
Insights
Synthetic Enzyme-Armed KillER (SEAKER) cells, engineered T cells that activate prodrugs, show efficacy against solid tumors. This adaptable platform, demonstrated in melanoma models, holds promise for diverse adoptive cell therapies in immunocompetent hosts.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Adoptively transferred T cells show promise for cancer treatment but struggle with solid tumors due to tumor heterogeneity and immune evasion.
- Existing engineered T cells, like chimeric antigen receptor (CAR) T cells, face limitations in complex host environments.
- Previous Synthetic Enzyme-Armed KillER (SEAKER) cells showed efficacy in lymphoma models but required testing in immunocompetent hosts for solid tumors.
Purpose of the Study:
- To develop and evaluate T-cell receptor (TCR)-engineered SEAKER cells for targeting solid-tumor melanomas in syngeneic mouse models.
- To assess the efficacy and host interactions of SEAKER cells in immunocompetent hosts.
- To demonstrate the broad applicability of the SEAKER platform for various adoptive cell therapies.
Main Methods:
- Engineering T cells with T-cell receptor (TCR) specificity for melanoma.
- Incorporating prodrug-activating enzymatic functions into SEAKER cells.
- Testing SEAKER cell efficacy and tumor localization in syngeneic, immunocompetent mouse models.
Main Results:
- TCR-engineered SEAKER cells specifically localized to solid tumor sites.
- SEAKER cells successfully activated bioactive prodrugs within the tumor microenvironment, overcoming host immune responses.
- The engineered SEAKER cells demonstrated significant efficacy in immunocompetent hosts, validating their therapeutic potential.
Conclusions:
- The SEAKER cell platform is effective against solid tumors, even in the presence of host immune responses.
- TCR-engineered SEAKER cells represent a versatile and potent tool for adoptive cell therapy.
- This technology holds significant promise for advancing cancer treatment strategies, particularly for solid tumors.
