Host Interactions with Engineered T-cell Micropharmacies.

TitleHost Interactions with Engineered T-cell Micropharmacies.
Publication TypeJournal Article
Year of Publication2023
AuthorsBourne CM, Wallisch P, Dacek MM, Gardner TJ, Pierre S, Vogt K, Corless BC, Bah MA, Romero-Pichardo JE, Charles A, Kurtz KG, Tan DS, Scheinberg DA
JournalCancer Immunol Res
Volume11
Issue9
Pagination1253-1265
Date Published2023 Sep 01
ISSN2326-6074
KeywordsAnimals, Genetic Engineering, Humans, Immunotherapy, Adoptive, Melanoma, Mice, Receptors, Antigen, T-Cell, T-Lymphocytes, Cytotoxic
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.

DOI10.1158/2326-6066.CIR-22-0879
Alternate JournalCancer Immunol Res
PubMed ID37379366
PubMed Central IDPMC10472090
Grant ListR01 CA055349 / CA / NCI NIH HHS / United States
T32 GM115327 / GM / NIGMS NIH HHS / United States
F31 CA254311 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
F31 CA261179 / CA / NCI NIH HHS / United States
T32 CA062948 / CA / NCI NIH HHS / United States
R35 CA241894 / CA / NCI NIH HHS / United States
T32 GM136640 / GM / NIGMS NIH HHS / United States
P01 CA023766 / CA / NCI NIH HHS / United States

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