Journal Article

DKFZ-2026-01364

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Depletion of CD8+ CAR T-cells leads to superior anti-tumor efficacy of pure CD4+ CAR T-cells against Acute Leukemias.

Chen, Q. ; Sedloev, D. ; Yao, H. ; Mao, L.DKFZ* ; Depke, D. ; Wang, L. ; Scheller, M. ; He, B. ; Liu, Y. ; Unglaub, J. M. ; Schmitt, A. ; Jayavelu, A. K.DKFZ* ; Tidow, C. M. ; Schmitt, M. ; Sauer, T.

2026
Elsevier Amsterdam

Abstract: Chimeric antigen receptor T-cell (CART) therapy has demonstrated clinical efficacy in hematologic malignancies; however, primary or secondary treatment failure remains major obstacles to durable responses. Defining the optimal cellular composition of CART products therefore represents a critical unmet need. Here, we show that CARTs targeting acute leukemias achieve maximal efficacy when composed exclusively of CD4+ T cells. Pure CD4+ CARTs exhibit superior antitumor activity and proliferation compared to CD8+-containing CART products. To elucidate the molecular basis of this functional divergence, we applied a combinatorial exploratory approach integrating bulk RNA sequencing and quantitative proteomics. Transcriptomic analyses revealed that pure CD4+ CARTs dopt a highly proliferative state characterized by a cytotoxic effector-like polarization. On the protein level, we are demonstrating coordinated loss of cell-cycle machinery and induction of apoptotic pathways in CD4+ CART cells co-cultured together with CD8+ CARTs, while pure CD4+ CART cultures maintained a proliferative, cytotoxic phenotype. Using mechanistically discriminative co-culture systems, we demonstrate that CD8+ CART-mediated impairment of CD4+ CART functionality is primarily driven by competitive access to shared antigen. Collectively, these findings identify antigen competition between CAR-T subsets as a previously unrecognized mechanism limiting CD4+ CART efficacy and provide a framework for optimizing CART product composition to enhance therapeutic persistence and durability.

Note: 2026 Aug 5;34(8):4687-4707

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Contributing Institute(s):

1. KKE Pädiatrische Leukämie (A400)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2026

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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