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.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, with current long-term survival rates upwards of 80% in the developed world [1]
To determine the potential of primary B cell precursor ALL (B-ALL) to respond directly to endosomal toll-like receptor (TLR) agonists, we evaluated leukemia cells from
As the degree of leukemia killing achieved was independent of TLR expression by B-ALL blasts, we evaluated the influence of the immune microenvironment on TLR-induced anti-leukemia activity in vivo using a panel of primary Eμ-ret leukemia samples that were not characterized for TLR expression
Summary
Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, with current long-term survival rates upwards of 80% in the developed world [1]. 20% of children whose leukemia recurs, the prognosis is significantly worse and treatment options are limited [1,2]. As greater than 95% of patients with ALL achieve a complete remission with contemporary chemotherapy, a pragmatic approach to improving overall outcome is to reduce the incidence of recurrence by applying novel therapy during the remission stage to further deplete leukemic blasts. While leukemia is subsequently eradicated from many MRD positive patients following intensified therapy, early MRD positivity is still associated with significantly poorer long-term outcome [7]
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