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Preprint WatchMildNovember 4th, 2026

Single-cell characterization of 3D CLL spheroid model that recapitulates lymph node microenvironment-driven phenotypes and in vivo drug responses to ibrutinib

Haselager, M. V.; Lashgari, D.; Jongejan, A.; Roos, J. L.; Dijkema, M.; Dubois, J.; Peters, F. S.; Kater, A. P.; Moerland, P. D.; Eldering, E.

Activated CLL cells showed relative resistance to ibrutinib, associated with TLR9-MALT1-MYC pathway activation.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

A single-cell study of a three-dimensional chronic lymphocytic leukemia spheroid model reports that activated CLL cells resist ibrutinib in association with TLR9, MALT1 and MYC pathway activation, which places MALT1 downstream of microenvironmental signaling in the same disease where the Claidex graph already holds a terminated MALT1 program. ONO-7018 reached Phase 1 in relapsed or refractory non-Hodgkin lymphoma and chronic lymphocytic leukemia before the sponsor discontinued it for strategic reprioritization rather than for any reported efficacy or safety result (ono-7018-malt1-nhl-cll-phase1-strategic-discontinuation). The preprint therefore contradicts no published failure, because no efficacy readout was ever published, and it strengthens the rationale for MALT1 inhibition in ibrutinib-resistant disease. Severity is mild on that basis: one prior program, stopped for portfolio reasons, with the mechanistic question still open.

Abstract excerpt

Lymph node (LN) microenvironmental signals promote chronic lymphocytic leukemia (CLL) cell survival, proliferation, and treatment resistance. We previously developed a 3D culture model that recapitulates key features of this protective LN niche. Using single-cell RNA sequencing of ex vivo paired peripheral blood and LN samples, together with matched patient-derived CLL spheroids, we investigated how microenvironmental cues shape CLL phenotypes and their response to ibrutinib. A total of 3 functional CLL states (resting, activated, proliferating) were identified, with expanded populations of activated and proliferating subsets in 3D cultures. After 5 days of in vitro ibrutinib treatment, CLL cells shifted toward a resting phenotype, reflecting published responses in patients at 6 months. Activated CLL cells showed relative resistance to ibrutinib, associated with TLR9-MALT1-MYC pathway activation. The 3D model recapitulated tissue-specific T cell phenotypes observed in patients, and computational analyses predicted several T-to-CLL cell-mediated interactions supporting the LN niche. Collectively, these data reveal distinct ibrutinib responses among CLL subsets and establish the 3D model as a physiologically relevant platform.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.