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[This article belongs to Volume - 71, Issue - 1]
Published on : 2026-01-20 01:10:44
Article Code: AMJ-20-01-2026-12362
Title : Armored Macrophage-Targeted CAR-T Cells Reset and Reprogram the Tumor Microenvironment and Control Metastatic Cancer Growth: A Phase I/II Clinical Trial
Author(s) : Elchin Mammadov
Abstract :
Background: Tumor-associated macrophages (TAMs), which commonly express triggering receptor expressed on
myeloid cells 2 (TREM2) or folate receptor beta (FOLR2), are enriched in solid tumors and maintain the tumor
microenvironment (TME) in an immunosuppressive state. Chimeric antigen receptor T-cell (CAR-T) therapies
targeting tumor cells directly have shown limited efficacy in solid malignancies due to antigen heterogeneity and the
immunosuppressive TME.
Methods: We engineered IL-12-expressing CAR-T cells targeting TREM2 or FOLR2 to deplete pro-tumor TAMs and
reprogram the TME. We conducted a Phase I/II clinical trial (NCT05987612) in patients with metastatic ovarian, lung,
breast, and pancreatic cancers. The primary endpoints were safety and feasibility; secondary endpoints included
objective response rate (ORR), progression-free survival (PFS), and biomarker analyses using spatial transcriptomics.
Results: Between January 2024 and October 2025, 42 patients received IL-12-armored anti-TAM CAR-T cells across
three dose levels. Treatment demonstrated a favorable safety profile with no dose-limiting toxicities at the highest
dose (1×10⁷ cells). The objective response rate was 75% (95% CI: 52-89), with 12 complete responses (28.6%). Median
PFS was 10.6 months (95% CI: 7.8-14.2). Spatial transcriptomics revealed sustained TME remodeling, with elimination
of TREM2+ macrophages, expansion of CXCL9+ immunostimulatory macrophages, and recruitment of endogenous
tumor-specific CD8+ cytotoxic T cells. Notably, tumor clearance was partially dependent on FAS expression on cancer
cells, revealing an IL-12-FAS axis for therapeutic activity.
Conclusions: IL-12-producing, myeloid-directed CAR-T cells represent a paradigm shift in solid tumor
immunotherapy. By targeting TAMs rather than cancer cells directly, this approach remodels the immunosuppressive
TME and generates durable anti-tumor immunity. These findings establish a new therapeutic strategy for metastatic
solid cancers refractory to conventional immunotherapy.