Host interactions with engineered T-cell micropharmacies Journal Article
| Authors: | Bourne, C. M.; Wallisch, P.; Dacek, M. M.; Gardner, T. J.; Pierre, S.; Vogt, K.; Corless, B. C.; Bah, M. A.; Romero-Pichardo, J. E.; Charles, A.; Kurtz, K. G.; Tan, D. S.; Scheinberg, D. A. |
| Article Title: | Host interactions with engineered T-cell micropharmacies |
| 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 Kill ER (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. |
| Keywords: | solid tumors; infiltration; humanized mice |
| Journal Title: | Cancer Immunology Research |
| Volume: | 11 |
| Issue: | 9 |
| ISSN: | 2326-6066 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2023-09-01 |
| Start Page: | 1253 |
| End Page: | 1265 |
| Language: | English |
| ACCESSION: | WOS:001122968400001 |
| DOI: | 10.1158/2326-6066.Cir-22-0879 |
| PROVIDER: | wos |
| PMCID: | PMC10472090 |
| PUBMED: | 37379366 |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: David A. Scheinberg -- Source: Wos |
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