T cell costimulation blockade for hyperacute steroid refractory graft versus-host disease in children undergoing haploidentical transplantation

Jaiswal, Sarita Rani; Zaman, Shamsuz; Chakrabarti, Aditi; Sehrawat, Amit; Bansal, Satish; Gupta, Mahesh; Chakrabarti, Suparno

doi:10.1016/j.trim.2016.08.009

Cited by 18 publications

(25 citation statements)

References 31 publications

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“…This technique was described earlier [2,13]. In brief, flow cytometric assessment was carried out on the donor leukapheresis products and on peripheral blood samples of patients at days + 30, +60, and +90 after HSCT.…”

Section: Flow Cytometric Assessment Of T and Nk Cell Subtypesmentioning

confidence: 99%

“…Intracellular staining for FoxP3 was carried out with mouse anti-human FoxP3 (259D/C7; BD Biosciences). Gating strategies were illustrated previously [2,13] and are shown in Supplementary Figures 1 to 3. The gating strategy for expression of CD80 and CD86 on NK cells was established on healthy donors using fluorescence minus 1 controls (see Supplementary Figure 4).…”

Section: Flow Cytometric Assessment Of T and Nk Cell Subtypesmentioning

confidence: 99%

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CTLA4Ig Primed Donor Lymphocyte Infusion: A Novel Approach to Immunotherapy after Haploidentical Transplantation for Advanced Leukemia

Jaiswal¹,

Bhakuni²,

Joy³

et al. 2019

Biology of Blood and Marrow Transplantation

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A B S T R A C T CTLA4Ig attenuates T cell activation by co-stimulation blockade, but natural killer (NK) cells are not only resistant to CTLA4Ig, they also may demonstrate better antileukemia effect in the presence of CTLA4Ig. To explore this phenomenon we used sequential CTLA4Ig primed donor lymphocyte infusion (DLI) after post-transplant cyclophos-phamideÀbased haploidentical transplantation. Thirty patients (CTLA4Ig-DLI group) with advanced leukemia received CTLA4Ig on day À1 and subsequently on days +7, +21, and +35, followed 12 hours later by DLI of 1 to 10 £ 10 6 CD3 + T cells/kg containing .1 to 3.27 £ 10 6 /kg CD56 + NK cells, with low dose cyclosporine for 60 days. The incidences of acute graft-versus-host disease (GVHD), chronic GVHD and nonrelapse mortality (NRM) were 6.7%, 21%, and 4.5 %, respectively, with disease progression of 23.3% and overall survival of 79% at 18 months. Patients without disease progression had a significant early surge in CD56 dim CD16 + NK cells with lower NKG2A expression. CTLA4Ig primed DLI was associated with an upregulation of CD86 in mature NK cells that was not witnessed with CTLA4Ig administration alone. Thus, CTLA4Ig primed DLI resulted in early proliferation of mature NK cells with cytotoxic potential enabling early institution of adoptive immunotherapy to mitigate the risk of relapse in advanced leukemia with reduced GVHD and NRM.

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Section: Flow Cytometric Assessment Of T and Nk Cell Subtypesmentioning

confidence: 99%

Section: Flow Cytometric Assessment Of T and Nk Cell Subtypesmentioning

confidence: 99%

CTLA4Ig Primed Donor Lymphocyte Infusion: A Novel Approach to Immunotherapy after Haploidentical Transplantation for Advanced Leukemia

Jaiswal¹,

Bhakuni²,

Joy³

et al. 2019

Biology of Blood and Marrow Transplantation

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“…The role of multiple costimulatory pathways has been studied in acute GVHD including the positive regulatory molecules promoting T‐cell activation‐like (Blazar et al , ), inducible costimulator (ICOS) (Taylor et al , ); Tumour necrosis factor receptor (TNFR)‐superfamily receptors (CD40LG, OX40, 4‐1BB) and negative regulatory molecules like cytotoxic T cell lymphocyte antigen (CTLA)‐4, Programmed death receptor (PD)‐1/PD‐L1 and PD‐L2 [reviewed in (Zeiser & Blazar, )]. In the clinical setting of hyperacute steroid‐refractory GVHD following haploidentical HSCT costimulatory blockade with abatacept was tested (Jaiswal et al , ). Five patients were treated with a combination of T cell costimulation blockade with abatacept, and etanercept and basiliximab.…”

Section: Costimulatory Pathways Chemokines and Cytokines In Acute Gvhdmentioning

confidence: 99%

“…Five patients were treated with a combination of T cell costimulation blockade with abatacept, and etanercept and basiliximab. The overall response at days 29 and 56 were 100% and 40% and the two patients achieving a complete remission were long‐term disease‐free survivors off immunosuppression (Jaiswal et al , ).…”

Section: Costimulatory Pathways Chemokines and Cytokines In Acute Gvhdmentioning

confidence: 99%

Advances in understanding the pathogenesis of graft‐versus‐host disease

Zeiser

2019

Br J Haematol

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Summary Acute graft‐versus‐host disease (GVHD) remains a major complication after allogeneic haematopoietic stem cell transplantation (allo‐HSCT). The emergence of different immuno‐prophylaxis strategies, such as post‐transplant cyclophosphamide or anti‐thymocyteglobulin has reduced the incidence of acute GVHD in recent years. The biology of the acute GVHD we observe in the clinic may change due to the use of novel immuno‐stimulatory agents, including immune checkpoint inhibitors or anti‐neoplastic immune‐modifiers, like lenalidomide, given before or after allo‐HSCT. Here we discuss the recent advances in our understanding of acute GVHD with a focus on early events of the disease, including tissue damaging factors, innate immune cells, costimulatory pathways, immune cell signalling, immuno‐regulatory cell types, biomarkers of GVHD and regenerative approaches. New insight in the pathogenesis of acute GVHD has revealed the role of pro‐inflammatory intracellular signalling, defects in intestinal tissue regeneration and anti‐bacterial defence, as well as a reduced diversity of the microbiome, which will be the basis for the development of novel therapies.

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“…Conditioning regimens for malignant and nonmalignant diseases have been described in detail in our previous publications [14][15][16]. All patients received PTCy as described previously.…”

Section: Conditioning Regimens and Gvhd Prophylaxismentioning

confidence: 99%

Higher CD45RA+ Regulatory T Cells in the Graft Improves Outcome in Younger Patients Undergoing T Cell–Replete Haploidentical Transplantation: Where Donor Age Matters

Jaiswal¹,

Bhakuni²,

Joy³

et al. 2018

Biology of Blood and Marrow Transplantation

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To understand the phenomenon of early alloreactivity (EA) in younger children undergoing post-transplantation cyclophosphamide (PTCy)-based haploidentical transplantation, we studied the graft composition and the immune reconstitution in 32 consecutive patients (aged 2 to 25 years) undergoing PTCy and T cell costimulation blockade based peripheral blood stem cell transplantation with emphasis on CD45RA subset of regulatory T cells (Tregs). All but 1 engrafted, and 14 patients experienced EA (acute graft-versus-host disease grades II to IV, n = 8; and post-transplantation hemophagocytic syndrome, n = 6) with a cumulative incidence of 43.7%; 42% developed mild chronic graft-versus-host disease. The overall survival was 70.2% with a nonrelapse mortality of 16.8% at a median of 19 months. Age < 10 years, donor age > 45 years, and poor recovery of Tregs correlated with EA. Not Tregs but higher CD45RA Tregs in the graft was associated with less EA (11.7% versus 32.5%, P = .0001). Higher donor age correlated with a lower CD45RA Tregs in the graft (P = .01). However, only higher CD45RA Treg percentage in the graft favorably impacted EA as well as nonrelapse mortality and overall survival. Our study demonstrates a critical role for CD45RA Tregs in determining EA and outcome after PTCy-based haploidentical peripheral blood stem cell transplantation, and the age-related physiologic decline in this population might be responsible for adverse impact of donor age.

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T cell costimulation blockade for hyperacute steroid refractory graft versus-host disease in children undergoing haploidentical transplantation

Cited by 18 publications

References 31 publications

CTLA4Ig Primed Donor Lymphocyte Infusion: A Novel Approach to Immunotherapy after Haploidentical Transplantation for Advanced Leukemia

CTLA4Ig Primed Donor Lymphocyte Infusion: A Novel Approach to Immunotherapy after Haploidentical Transplantation for Advanced Leukemia

Advances in understanding the pathogenesis of graft‐versus‐host disease

Higher CD45RA+ Regulatory T Cells in the Graft Improves Outcome in Younger Patients Undergoing T Cell–Replete Haploidentical Transplantation: Where Donor Age Matters

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