Generation of a multi-antigen-directed immune response for durable control of acute lymphoblastic leukemia

Jo, Sumin; Lee, J H; Mattei, Jane; Barrett, David M.; Grupp, Stephan A.; Reid, Gavin D.; Seif, Alix E.

doi:10.1038/leu.2017.290

Cited by 5 publications

(4 citation statements)

References 15 publications

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“…However, BCP blasts isolated from moribund NSG recipients of preleukemia quickly progressed to full blown disease in secondary BALB/c recipients (Fig. 1H, right panel), consistent with the rapid outgrowth observed in BALB/c mice engrafted with primary leukemia from Eμ-Ret mice [37,38]. This result confirms that the early-arising preleukemic BCP population is sufficient for leukemia generation and indicates that the engraftment and/or progression of preleukemia may be influenced by the immune status of the recipient mice.…”

Section: Resultssupporting

confidence: 73%

The Eμ-Ret mouse is a novel model of hyperdiploid B-cell acute lymphoblastic leukemia

Farrokhi,

Atre,

Rever

et al. 2024

Leukemia

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The presence of supernumerary chromosomes is the only abnormality shared by all patients diagnosed with high-hyperdiploid B cell acute lymphoblastic leukemia (HD-ALL). Despite being the most frequently diagnosed pediatric leukemia, the lack of clonal molecular lesions and complete absence of appropriate experimental models have impeded the elucidation of HD-ALL leukemogenesis. Here, we report that for 23 leukemia samples isolated from moribund Eμ-Ret mice, all were characterized by non-random chromosomal gains, involving combinations of trisomy 9, 12, 14, 15, and 17. With a median gain of three chromosomes, leukemia emerged after a prolonged latency from a preleukemic B cell precursor cell population displaying more diverse aneuploidy. Transition from preleukemia to overt disease in Eμ-Ret mice is associated with acquisition of heterogeneous genomic abnormalities affecting the expression of genes implicated in pediatric B-ALL. The development of abnormal centrosomes in parallel with aneuploidy renders both preleukemic and leukemic cells sensitive to inhibitors of centrosome clustering, enabling targeted in vivo depletion of leukemia-propagating cells. This study reveals the Eμ-Ret mouse to be a novel tool for investigating HD-ALL leukemogenesis, including supervision and selection of preleukemic aneuploid clones by the immune system and identification of vulnerabilities that could be targeted to prevent relapse.

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Section: Resultssupporting

confidence: 73%

The Eμ-Ret mouse is a novel model of hyperdiploid B-cell acute lymphoblastic leukemia

Farrokhi,

Atre,

Rever

et al. 2024

Leukemia

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“…Using syngeneic murine models of pre-B-cell ALL in immune competent mice, we demonstrate that T-cell dysfunction is induced by progressive leukemia and that this can impact the efficacy of immunotherapeutic approaches that rely on T cells residing in the leukemic host. T-cell depletion has been associated with loss of protection in a syngeneic murine 36 model, and our data extend this observation to the context of vaccines and CARTs. Furthermore, we establish that T-cell dysfunction is initiated early in the course of leukemia progression, precluding efficacy of a therapeutic vaccine.…”

Section: Discussionsupporting

confidence: 78%

Murine pre–B-cell ALL induces T-cell dysfunction not fully reversed by introduction of a chimeric antigen receptor

Qin

Ishii

Nguyen

et al. 2018

Blood

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Adoptive transfer of patient-derived T cells modified to express chimeric antigen receptors (CARTs) has demonstrated dramatic success in relapsed/refractory pre-B-cell acute lymphoblastic leukemia (ALL), but response and durability of remission requires exponential CART expansion and persistence. Tumors are known to affect T-cell function, but this has not been well studied in ALL and in the context of chimeric antigen receptor (CAR) expression. Using TCF3/PBX1 and MLL-AF4-driven murine ALL models, we assessed the impact of progressive ALL on T-cell function in vivo. Vaccines protect against TCF3/PBX1.3 but were ineffective when administered after leukemia injection, suggesting immunosuppression induced early during ALL progression. T cells from leukemia-bearing mice exhibited increased expression of inhibitory receptors, including PD1, Tim3, and LAG3, and were dysfunctional following adoptive transfer in a model of T-cell receptor (TCR)-dependent leukemia clearance. Although expression of inhibitory receptors has been linked to TCR signaling, pre-B-cell ALL induced inhibitory receptor expression, at least in part, in a TCR-independent manner. Finally, introduction of a CAR into T cells generated from leukemia-bearing mice failed to fully reverse poor in vivo function.

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“…The ability of TLR agonists to induce such protective immune activity in mice receiving conventional ALL chemotherapy drugs should now be assessed. Furthermore, given the ability of CTLA4 blockade to prolong survival of Eµ-ret mice [39], the superior immunostimulatory ability of CpG ODN to elicit durable protection against leukemia outgrowth demonstrated in this study provides additional support for investigating checkpoint inhibitors in combination with TLR agonists to maximize therapeutic efficacy. Such productive immune-stimulatory approaches may also enhance epitope spreading after CAR-T therapy, a phenomenon that may contribute to the maintenance of B-ALL remissions [39].…”

Section: Discussionmentioning

confidence: 80%

“…Leukemia-involved spleens were processed with Tris-buffered ammonium chloride (TAC; pH: 7.2) to lyse red blood cells. The characteristic Eµ-ret B cell precursor leukemic cell phenotype (B220 int /BP-1 hi ) was used to identify and quantify leukemic cell populations in all cases by flow cytometry [39].…”

Section: Cellsmentioning

confidence: 99%

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

Fotovati

Duque‐Afonso

et al. 2020

Cancers

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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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Generation of a multi-antigen-directed immune response for durable control of acute lymphoblastic leukemia

Cited by 5 publications

References 15 publications

The Eμ-Ret mouse is a novel model of hyperdiploid B-cell acute lymphoblastic leukemia

The Eμ-Ret mouse is a novel model of hyperdiploid B-cell acute lymphoblastic leukemia

Murine pre–B-cell ALL induces T-cell dysfunction not fully reversed by introduction of a chimeric antigen receptor

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

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