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Differential Depletion of Bone Marrow Resident B-ALL after Systemic Administration of Endosomal TLR Agonists

Authors
  • Jo, Sumin1
  • Fotovati, Abbas1
  • Duque-Afonso, Jesus2
  • Cleary, Michael L.2
  • van den Elzen, Peter
  • Seif, Alix E.
  • Reid, Gregor S.D.1, 3
  • 1 (A.F.)
  • 2 (M.L.C.)
  • 3 Department of Pediatrics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
Type
Published Article
Journal
Cancers
Publisher
MDPI AG
Publication Date
Jan 10, 2020
Volume
12
Issue
1
Identifiers
DOI: 10.3390/cancers12010169
PMID: 32015298
PMCID: PMC7016792
Source
PubMed Central
Keywords
License
Green

Abstract

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. While frontline chemotherapy regimens are generally very effective, the prognosis for patients whose leukemia returns remains poor. The presence of measurable residual disease (MRD) in bone marrow at the completion of induction therapy is the strongest predictor of relapse, suggesting that strategies to eliminate the residual leukemic blasts from this niche could reduce the incidence of recurrence. We have previously reported that toll-like receptor (TLR) agonists achieve durable T cell-mediated protection in transplantable cell line-based models of B cell precursor leukemia (B-ALL). However, the successful application of TLR agonist therapy in an MRD setting would require the induction of anti-leukemic immune activity specifically in the bone marrow, a site of the chemotherapy-resistant leukemic blasts. In this study, we compare the organ-specific depletion of human and mouse primary B-ALL cells after systemic administration of endosomal TLR agonists. Despite comparable splenic responses, only the TLR9 agonist induced strong innate immune responses in the bone marrow and achieved a near-complete elimination of B-ALL cells. This pattern of response was associated with the most significantly prolonged disease-free survival. Overall, our findings identify innate immune activity in the bone marrow that is associated with durable TLR-induced protection against B-ALL outgrowth.

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