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[This article belongs to Volume - 71, Issue - 1]
Published on : 2026-01-20 01:26:03
Article Code: AMJ-20-01-2026-12365
Title : Tumor-Antigen-Independent Targeting of Solid Tumors by Armored Macrophage-Directed Anti-TREM2 CAR T Cells: Mechanistic Insights and Clinical Applications
Author(s) : Dr. Kamal Huseynov
Abstract :
Background: Solid tumors present unique challenges for chimeric antigen receptor (CAR) T-cell therapy due to
antigen heterogeneity and the immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages
(TAMs) expressing triggering receptor expressed on myeloid cells 2 (TREM2) are critical orchestrators of
immunosuppression across diverse tumor types. We hypothesized that targeting TREM2+ macrophages rather than
tumor cells directly could overcome barriers to CAR-T efficacy in solid malignancies.
Methods: We engineered IL-12-armored anti-TREM2 CAR T cells (aTREM2-CAR) and evaluated their efficacy in
preclinical models of ovarian, lung, and pancreatic cancers. Single-cell RNA sequencing, spatial transcriptomics, and
multiparametric flow cytometry were employed to characterize TME remodeling. A Phase I clinical trial was
conducted in 18 patients with advanced platinum-resistant ovarian cancer.
Results: aTREM2-CAR T cells demonstrated robust expansion and persistence in vivo, effectively depleting TREM2+
immunosuppressive macrophages while promoting pro-inflammatory CXCL9+ macrophage polarization. Unlike
tumor-targeting CAR-T cells, antigen escape was not observed. In ovarian cancer models, aTREM2-CAR induced
complete responses in 75% of mice, with 40% maintaining long-term remission beyond 12 months. Mechanistically,
IL-12 secretion activated the STING pathway, enhanced cross-presentation, and recruited endogenous CD8+ cytotoxic
T cells. In the clinical trial, 11 of 18 patients (61%) achieved objective responses, with 3 complete metabolic
responses. Median progression-free survival was 8.4 months. Toxicity was manageable, with no Grade ≥3 cytokine
release syndrome observed.
Conclusions: Armored macrophage-directed CAR T cells represent a paradigm shift in solid tumor immunotherapy,
offering a tumor-antigen-independent approach that remodels the TME and engages endogenous immunity. Clinical
efficacy in platinum-resistant ovarian cancer supports further development across solid tumor indications.