Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Combining SiRPα decoy–coengineered T cells and antibodies augments macrophage-mediated phagocytosis of tumor cells
Evangelos Stefanidis, … , George Coukos, Melita Irving
Evangelos Stefanidis, … , George Coukos, Melita Irving
Published June 3, 2024
Citation Information: J Clin Invest. 2024;134(11):e161660. https://doi.org/10.1172/JCI161660.
View: Text | PDF
Research Article Immunology Article has an altmetric score of 72

Combining SiRPα decoy–coengineered T cells and antibodies augments macrophage-mediated phagocytosis of tumor cells

  • Text
  • PDF
Abstract

The adoptive transfer of T cell receptor–engineered (TCR-engineered) T cells (ACT) targeting the HLA-A2–restricted cancer-testis epitope NY-ESO-1157–165 (A2/NY) has yielded favorable clinical responses against several cancers. Two approaches to improve ACT are TCR affinity optimization and T cell coengineering to express immunomodulatory molecules that can exploit endogenous immunity. By computational design we previously developed a panel of binding-enhanced A2/NY-TCRs including A97L, which augmented the in vitro function of gene-modified T cells as compared with WT. Here, we demonstrated higher persistence and improved tumor control by A97L–T cells. In order to harness macrophages in tumors, we further coengineered A97L–T cells to secrete a high-affinity signal regulatory protein α (SiRPα) decoy (CV1) that blocks CD47. While CV1-Fc–coengineered A97L–T cells mediated significantly better control of tumor outgrowth and survival in Winn assays, in subcutaneous xenograft models the T cells, coated by CV1-Fc, were depleted. Importantly, there was no phagocytosis of CV1 monomer–coengineered T cells by human macrophages. Moreover, avelumab and cetuximab enhanced macrophage-mediated phagocytosis of tumor cells in vitro in the presence of CV1 and improved tumor control upon coadministration with A97L–T cells. Taken together, our study indicates important clinical promise for harnessing macrophages by combining CV1-coengineered TCR–T cells with targeted antibodies to direct phagocytosis against tumor cells.

Authors

Evangelos Stefanidis, Aikaterini Semilietof, Julien Pujol, Bili Seijo, Kirsten Scholten, Vincent Zoete, Olivier Michielin, Raphael Sandaltzopoulos, George Coukos, Melita Irving

×

Figure 2

Affinity-enhanced A97L-TCR-T cells significantly improve tumor control and survival.

Options: View larger image (or click on image) Download as PowerPoint
Affinity-enhanced A97L-TCR-T cells significantly improve tumor control a...
(A) Schematic of ACT study. (B) Control of A375 tumors (left) in NSG mice and survival curves (right) following ACT (n = 6 mice per group; data are representative of 2 independent studies). (C) Number of intratumoral human CD8+ (left) and CD4+ (right) T cells per milligram of tumor 7 days after ACT (n = 5; data are representative of 2 independent studies). (D) Ratio of intratumoral CD8+/CD4+ human T cell frequency 7 days after ACT (n = 5; data are representative of 2 independent studies). (E) Frequency (left) and geometric mean fluorescence intensity (G-MFI) (right) of Ki-67 expression within intratumoral human CD8+ T cells 7 days after ACT (n ≥4; data are representative of 2 independent studies). (F) Number of intratumoral mouse F4-80hi macrophages per milligram of tumor 7 days after ACT (n = 5; data are representative of 2 independent studies). (G) G-MFI of mouse SiRPα expression within intratumoral mouse F4-80hi macrophages 7 days after ACT (n = 5; data are representative of 2 independent studies). Statistical analysis was done by 2-way ANOVA (B, left), Mantel-Cox (B, right), or 1-way ANOVA (C–G) with correction for multiple comparisons by post hoc Tukey’s test (B–G). *P < 0.05; **P < 0.01; ***P < 0.001; ****P< 0.0001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 10 news outlets
Blogged by 1
Posted by 9 X users
On 1 Facebook pages
6 readers on Mendeley
See more details