New anti-IL-7Rα monoclonal antibodies show efficacy against T cell acute lymphoblastic leukemia in pre-clinical models

Hixon, Julie A.; Andrews, Caroline; Kashi, Lila; Kohnhorst, Casey; Senkevitch, Emilee; Czarra, Kelli; Barata, João T.; Li, Wenqing; Schneider, Joel P.; Walsh, Scott T. R.; Durum, Scott K.

doi:10.1038/s41375-019-0531-8

Cited by 27 publications

(23 citation statements)

References 42 publications

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“…11c). As NSG mice lack NK cells, we excluded that it led to cell death via antibodydependent cell-mediated cytotoxicity as previously described by other IL7R antibodies 39 . Similarly, the antibody which we used does not block IL7 binding ( Supplementary Fig.…”

Section: Bcr-abl1 Controls Il7r Expression By Regulating Foxo1mentioning

confidence: 99%

Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia

et al. 2020

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Ph + acute lymphoblastic leukemia (ALL) is characterized by the expression of an oncogenic fusion kinase termed BCR-ABL1. Here, we show that interleukin 7 receptor (IL7R) interacts with the chemokine receptor CXCR4 to recruit BCR-ABL1 and JAK kinases in close proximity. Treatment with BCR-ABL1 kinase inhibitors results in elevated expression of IL7R which enables the survival of transformed cells when IL7 was added together with the kinase inhibitors. Importantly, treatment with anti-IL7R antibodies prevents leukemia development in xenotransplantation models using patient-derived Ph + ALL cells. Our results suggest that the association between IL7R and CXCR4 serves as molecular platform for BCR-ABL1-induced transformation and development of Ph + ALL. Targeting this platform with anti-IL7R antibody eliminates Ph + ALL cells including those with resistance to commonly used ABL1 kinase inhibitors. Thus, anti-IL7R antibodies may provide alternative treatment options for ALL in general and may suppress incurable drug-resistant leukemia forms.

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Section: Bcr-abl1 Controls Il7r Expression By Regulating Foxo1mentioning

confidence: 99%

Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia

et al. 2020

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“…Several anti-IL-7Rα blocking mAbs are currently in Phase I or Phase IIa trials in patients with autoimmune diseases where IL-7R seems to play a critical role (reviewed in [ 249 ]), such as type 1 diabetes and multiple sclerosis, or Sjogren’s syndrome and inflammatory bowel disease, respectively (reviewed in [ 250 ]). In T-ALL, PDX models based on administration of anti-IL-7Rα mAbs and ADCs have provided promising results for therapeutic targeting of T-ALLs expressing either wild type or mutant IL-7Rs [ 251 , 252 ], and preclinical studies have also proved that mAb-mediated IL-7R targeting impairs B-ALL progression and metastasis [ 253 ]. Recently, Barata and co-workers [ 251 ] have generated a fully human mAb that recognizes human IL-7Rα and impairs IL-7/IL-7R-mediated signaling.…”

Section: Potential New Targets For T-all Immunotherapymentioning

confidence: 99%

“…Conjugation with the antineoplastic toxin monomethyl auristatin E (MMAE) significantly increased the leukemia killing capacity of the mAb, validating the ADC approach. Additional work by Durum and coworkers showed that anti-IL-7Rα mAb-mediated ADCC had therapeutic efficacy against both relapsing and established disease in T-ALL preclinical models [ 252 ], leaving the door open for clinical trials evaluating the efficacy of this therapeutic strategy in unresponsive and relapsed patients.…”

Section: Potential New Targets For T-all Immunotherapymentioning

confidence: 99%

Facts and Challenges in Immunotherapy for T-Cell Acute Lymphoblastic Leukemia

Bayón-Calderón

Toribio

González-García

2020

IJMS

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T-cell acute lymphoblastic leukemia (T-ALL), a T-cell malignant disease that mainly affects children, is still a medical challenge, especially for refractory patients for whom therapeutic options are scarce. Recent advances in immunotherapy for B-cell malignancies based on increasingly efficacious monoclonal antibodies (mAbs) and chimeric antigen receptors (CARs) have been encouraging for non-responding or relapsing patients suffering from other aggressive cancers like T-ALL. However, secondary life-threatening T-cell immunodeficiency due to shared expression of targeted antigens by healthy and malignant T cells is a main drawback of mAb—or CAR-based immunotherapies for T-ALL and other T-cell malignancies. This review provides a comprehensive update on the different immunotherapeutic strategies that are being currently applied to T-ALL. We highlight recent progress on the identification of new potential targets showing promising preclinical results and discuss current challenges and opportunities for developing novel safe and efficacious immunotherapies for T-ALL.

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“…V H and C H1 fragments of AMG157 Fab are colored in violet blue and the V L -C L fragments in white blue and shown as cartoons on a transparent gray surface representation. (B) Cartoon representation of the IL-7:IL-7Rα:4A10 Fab :2B8 Fab by superposition of IL-7Rα:4A10 Fab and IL-7Rα:2B8 Fab and IL-7:IL-7Rα based on structural alignment of IL-7Rα chains [PDB ID 3DI2, 6P50, 6P67 ( 99 , 139 )]. IL-7 is shown in pink cartoon representation with four helices marked αA-αD on a transparent gray surface representation.…”

Section: Modulators Of Tslp Signalingmentioning

confidence: 99%

Modulation of Signaling Mediated by TSLP and IL-7 in Inflammation, Autoimmune Diseases, and Cancer

Marković

Savvides

2020

Front. Immunol.

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Thymic Stromal Lymphopoietin (TSLP) and Interleukin-7 (IL-7) are widely studied cytokines within distinct branches of immunology. On one hand, TSLP is crucially important for mediating type 2 immunity at barrier surfaces and has been linked to widespread allergic and inflammatory diseases of the airways, skin, and gut. On the other hand, IL-7 operates at the foundations of T-cell and innate lymphoid cell (ILC) development and homeostasis and has been associated with cancer. Yet, TSLP and IL-7 are united by key commonalities in their structure and the structural basis of the receptor assemblies they mediate to initiate cellular signaling, in particular their cross-utilization of IL-7Rα. As therapeutic targeting of TSLP and IL-7 via diverse approaches is reaching advanced stages and in light of the plethora of mechanistic and structural data on receptor signaling mediated by the two cytokines, the time is ripe to provide integrated views of such knowledge. Here, we first discuss the major pathophysiological roles of TSLP and IL-7 in autoimmune diseases, inflammation and cancer. Subsequently, we curate structural and mechanistic knowledge about receptor assemblies mediated by the two cytokines. Finally, we review therapeutic avenues targeting TSLP and IL-7 signaling. We envision that such integrated view of the mechanism, structure, and modulation of signaling assemblies mediated by TSLP and IL-7 will enhance and fine-tune the development of more effective and selective approaches to further interrogate the role of TSLP and IL-7 in physiology and disease.

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New anti-IL-7Rα monoclonal antibodies show efficacy against T cell acute lymphoblastic leukemia in pre-clinical models

Cited by 27 publications

References 42 publications

Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia

Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia

Facts and Challenges in Immunotherapy for T-Cell Acute Lymphoblastic Leukemia

Modulation of Signaling Mediated by TSLP and IL-7 in Inflammation, Autoimmune Diseases, and Cancer

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