Dose-escalated interleukin-2 therapy for refractory chronic graft-versus-host disease in adults and children

Whangbo, Jennifer; Kim, Haesook T.; Mirkovic, Nikola V.; Leonard, Lauren; Poryanda, Samuel J.; Silverstein, Sophie; Kim, Soomin; Reynolds, Carol; Sharmila, C.; Verrill, Kelly; Lee, Michelle A.; Margossian, Steven; Duncan, Christine; Lehmann, Leslie; Huang, Jennifer T.; Nikiforow, Sarah; Alyea, Edwin P.; Armand, Philippe; Cutler, Corey; Ho, Vincent T.; Blazar, Bruce R.; Antin, Joseph H.; Soiffer, Robert J.; Ritz, Jérôme; Koreth, John

doi:10.1182/bloodadvances.2019000631

Cited by 50 publications

(47 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although dose-escalation was well-tolerated by children with partial response (PR) in 82% of patients, only 2/7 evaluable adult patients showed PR and a dose-escalation above the previously defined maximum tolerated dose could not improve the clinical outcome. 66 …”

Section: Il-2 Treatmentmentioning

confidence: 99%

Immunomodulatory Therapies for the Treatment of Graft-versus-host Disease

Braun

Zeiser

2021

HemaSphere

View full text Add to dashboard Cite

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative therapy for patients suffering from hematological malignancies, and its therapeutic success is based on the graft-versus-leukemia (GvL) effect. Severe acute and chronic graft-versushost disease (GvHD) are life-threatening complications after allo-HCT. To date, most of the approved treatment strategies for GvHD rely on broadly immunosuppressive regimens, which limit the beneficial GvL effect by reducing the cytotoxicity of anti-leukemia donor T-cells. Therefore, novel therapeutic strategies that rely on immunomodulatory rather than only immunosuppressive effects could help to improve patient outcomes. Treatments should suppress severe GvHD while preserving anti-leukemia immunity. New treatment strategies include the blockade of T-cell activation via inhibition of dipeptidyl peptidase 4 and cluster of differentiation 28-mediated co-stimulation, reduction of proinflammatory interleukin (IL)-2, IL-6 and tumor necrosis factor-α signaling, as well as kinase inhibition. Janus kinase (JAK)1/2 inhibition acts directly on T-cells, but also renders antigen presenting cells more tolerogenic and blocks dendritic cell-mediated T-cell activation and proliferation. Extracorporeal photopheresis, hypomethylating agent application, and lowdose IL-2 are powerful approaches to render the immune response more tolerogenic by regulatory T-cell induction. The transfer of immunomodulatory and immunosuppressive cell populations, including mesenchymal stromal cells and regulatory T-cells, showed promising results in GvHD treatment. Novel experimental procedures are based on metabolic reprogramming of donor T-cells by reducing glycolysis, which is crucial for cytotoxic T-cell proliferation and activity.

show abstract

Section: Il-2 Treatmentmentioning

confidence: 99%

Immunomodulatory Therapies for the Treatment of Graft-versus-host Disease

Braun

Zeiser

2021

HemaSphere

View full text Add to dashboard Cite

show abstract

“…Imbalance between effector and regulatory cells supported by Tfh dysregulation is one of the key mechanisms leading to a breakdown in immune tolerance in auto-immune diseases. Since IL-2 could promote the maintenance of regulatory T cells (Treg), some studies based on IL-2 therapy for the treatment of auto-immune disease or cGVHD have been published [ 82 – 84 ]. In SLE patients, the lack of IL-2 and the imbalance between Tfh and Treg cells could be restored after low dose IL-2 treatment [ 85 , 86 ].…”

Section: Targeting Tfh In Systemic Sclerosis: Perspectives From Other Auto-immune Diseases and Gvhd Modelsmentioning

confidence: 99%

TFH cells in systemic sclerosis

et al. 2021

View full text Add to dashboard Cite

Systemic sclerosis is an autoimmune disease characterized by excessive dermal fibrosis with progression to internal organs, vascular impairment and immune dysregulation evidenced by the infiltration of inflammatory cells in affected tissues and the production of auto antibodies. While the pathogenesis remains unclear, several data highlight that T and B cells deregulation is implicated in the disease pathogenesis. Over the last decade, aberrant responses of circulating T follicular helper cells, a subset of CD4 T cells which are able to localise predominantly in the B cell follicles through a high level of chemokine receptor CXCR5 expression are described in pathogenesis of several autoimmune diseases and chronic graft-versus-host-disease. In the present review, we summarized the observed alteration of number and frequency of circulating T follicular helper cells in systemic sclerosis. We described their role in aberrant B cell activation and differentiation though interleukine-21 secretion. We also clarified T follicular helper-like cells involvement in fibrogenesis in both human and mouse model. Finally, because T follicular helper cells are involved in both fibrosis and autoimmune abnormalities in systemic sclerosis patients, we presented the different strategies could be used to target T follicular helper cells in systemic sclerosis, the therapeutic trials currently being carried out and the future perspectives from other auto-immune diseases and graft-versus-host-disease models.

show abstract

“…Dose escalation and/or IST combination approaches are being investigated in both pediatric and adult SR-cGVHD. 122 However, it has been noted that efficacy diminishes once therapy is completed, potentially requiring patients to adhere to chronic systemic IL-2 treatment until immune tolerance is achieved.…”

Section: Low-dose Il-2mentioning

confidence: 99%

Evolving Therapeutic Options for Chronic Graft‐versus‐Host Disease

Gonzalez

Pidala

2020

Pharmacotherapy

View full text Add to dashboard Cite

Despite improvements in prevention and treatment of acute graft‐versus‐host disease (GVHD), chronic GVHD (cGVHD) remains a significant contributor to morbidity and mortality of allogeneic transplant patients. Chronic GVHD remains a leading cause of late complications posttransplant and is impacted by donor‐, patient‐, and transplant‐related (hematopoietic cell transplant [HCT]) factors. Advances in the biological understanding of cGVHD have provided opportunities to improve clinical interventions for prevention and treatment. Expansion of posttransplantation cyclophosphamide beyond haploidentical HCTs has transformed alternative donor, matched, and mismatch GVHD outcomes and is currently being investigated in two upcoming clinical trials network prophylaxis studies. Although corticosteroids remain the cornerstone therapy, several clinical trials are prospectively investigating the utility of using novel agents in combination with corticosteroids as upfront therapy to mitigate prolonged steroid exposure. Several treatment options for patients with steroid‐refractory cGVHD are currently being investigated, and advances have resulted in ibrutinib becoming the first cGVHD agent approved by the U.S. Food and Drug Administration. We review recent advances in understanding of cGVHD pathophysiology and new approaches for the prevention and treatment of cGVHD.

show abstract

Dose-escalated interleukin-2 therapy for refractory chronic graft-versus-host disease in adults and children

Cited by 50 publications

References 35 publications

Immunomodulatory Therapies for the Treatment of Graft-versus-host Disease

Immunomodulatory Therapies for the Treatment of Graft-versus-host Disease

TFH cells in systemic sclerosis

Evolving Therapeutic Options for Chronic Graft‐versus‐Host Disease

Contact Info

Product

Resources

About