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
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
  1. Derek S Tan
    92 Tan
  2. Megan Dacek
    17 Dacek
  3. Christopher Bourne
    13 Bourne
  4. Thomas J Gardner
    13 Gardner
  5. Keifer Gary Kurtz
    11 Kurtz
  6. Kristen Catherine Vogt
    6 Vogt
  7. Stephanie Pierre
    5 Pierre
  8. Mamadou Alpha Bah
    1 Bah