Host Interactions with Engineered T-cell Micropharmacies.

Publication Type	Academic Article
Authors	Bourne C, Wallisch P, Dacek M, Gardner T, Pierre S, Vogt K, Corless B, Bah M, Romero-Pichardo J, Charles A, Kurtz K, Tan D, Scheinberg D
Journal	Cancer Immunol Res
Volume	11
Issue	9
Pagination	1253-1265
Date Published	09/01/2023
ISSN	2326-6074
Keywords	Immunotherapy, Adoptive, Melanoma
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.
DOI	10.1158/2326-6066.CIR-22-0879
PubMed ID	37379366
PubMed Central ID	PMC10472090