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

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.

BAX as the mediator of C-MYC sensitizes acute lymphoblastic leukemia to TLR9 agonists

“…However, the safety and effectiveness of their application still need attention. As an immune adjuvant, CpG ODN has shown good efficacy in removing B-ALL MRD by promoting anticancer immunity and is superior to other TLR agonists [ 5 ]. However, the direct effect of CpG ODNs on B-ALL is still lacking in relevant studies.…”

“…Immunotherapy, as an effective therapy for the elimination of MRD, can significantly reduce the recurrence of B-ALL [ 3 , 4 ]. Indeed, owing to the low immunogenicity of B-ALL cells, the effect of current immunotherapy is still limited [ 5 ]. Even though T cells with chimeric antigen receptors have improved the response rate of B-ALL from 30 to 90% [ 6 ], toxicity also limits its use [ 7 , 8 ].…”

Continuous Complete Remission in Two Patients with Acute Lymphoblastic Leukemia and Severe Fungal Infection Following Short-Term, Dose-Reduced Chemotherapy

“…Also, in a breast cancer model, intratumoral dendritic cells could enhance efficacy of anthracyclines highlighting the interaction of immune cells and cytotoxic therapy ( Vacchelli et al, 2015 ). In animal models, TLR9 stimulation triggers the break of tumor tolerance and induces immunity against AML and ALL ( Hossain et al, 2014 ; Jo et al, 2020 ). A phase I trial with the TLR9 agonist (GNKG168) supports the immunomodulatory capacity of a TLR9 agonists in vivo, showing that in children with acute leukemia and present minimal residual disease a unique immune activation pattern can be induced ( Ronsley et al, 2019 ).…”

The Role of Toll-like Receptor Agonists and Their Nanomedicines for Tumor Immunotherapy

“…The TLR9 agonist, CpG-oligodeoxynucleotides (CpG-ODN), a synthetic bacterial sequence derived nucleotides with a phosphorothioate backbone chain and repeated CpG motif [57], serves as a promising target for innate immune response in the bone marrow and the almost complete elimination of B-ALL cells [58]. Meanwhile, CpG-ODN (GNKG168) was discovered to be involved in checkpoint signal suppression and upgrading in T cells, B cells, and innate immune responses in pediatric leukemia patients [59].…”