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

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 induct...

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Veröffentlicht in:Cancers 2020-01, Vol.12 (1), p.169
Hauptverfasser: Jo, Sumin, Fotovati, Abbas, Duque-Afonso, Jesus, Cleary, Michael L, van den Elzen, Peter, Seif, Alix E, Reid, Gregor S D
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container_issue 1
container_start_page 169
container_title Cancers
container_volume 12
creator Jo, Sumin
Fotovati, Abbas
Duque-Afonso, Jesus
Cleary, Michael L
van den Elzen, Peter
Seif, Alix E
Reid, Gregor S D
description 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.
doi_str_mv 10.3390/cancers12010169
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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. 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source Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; MDPI - Multidisciplinary Digital Publishing Institute; PubMed Central
subjects Acute lymphoblastic leukemia
Agonists
Bone marrow
Cell culture
Chemotherapy
Cytotoxicity
Induction therapy
Innate immunity
Leukemia
Lymphatic leukemia
Lymphocytes
Lymphocytes T
Malignancy
Medical prognosis
Patients
Pediatrics
Spleen
TLR9 protein
Toll-like receptors
title Differential Depletion of Bone Marrow Resident B-ALL after Systemic Administration of Endosomal TLR Agonists
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