Persis Amrolia

Great Ormond Street Hospital for Children NHS Foundation Trust, Londinium, England, United Kingdom

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Publications (94)630.93 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Unrelated cord blood transplantation (CBT) without in vivo T-cell depletion is increasingly used to treat high-risk haematological malignancies. Following T-replete CBT, naïve cord blood (CB) T cells undergo rapid peripheral expansion with memory-effector differentiation. Emerging data suggest that unrelated CBT, particularly in the context of HLA-mismatch and a T-replete graft, may reduce leukemic relapse. To study the role of CB T cells in mediating graft-versus-tumor responses and dissect the underlying immune mechanisms for this, we compared the ability of HLA-mismatched CB and adult peripheral blood (PB) T cells to eliminate Epstein-Barr virus (EBV)-driven human B-cell lymphoma in a xenogeneic NOD/SCID/IL2rg(null) mouse model. CB T cells mediated enhanced tumor rejection compared to equal numbers of PB T cells, leading to improved survival in the CB group (p<0.0003). Comparison of CB T cells that were autologous vs allogeneic to the lymphoma demonstrated that this anti-tumor effect was mediated by alloreactive rather than EBV-specific T cells. Analysis of tumor-infiltrating lymphocytes demonstrated that CB T cells mediated this enhanced anti-tumor effect by rapid infiltration of the tumor with CCR7+ CD8+ T cells and prompt induction of cytotoxic CD8+ and CD4+ Th1 T cells in the tumor microenvironment. In contrast, in the PB group, this anti-lymphoma effect is impaired because of delayed tumoral infiltration of PB T cells and a relative bias toward suppressive Th2 and T-regulatory cells. Our data suggest that, despite being naturally programmed toward tolerance, reconstituting T cells after unrelated T-replete CBT may provide superior Tc1-Th1 anti-tumor effects against high-risk hematological malignancies.
    Blood 10/2015; DOI:10.1182/blood-2015-06-654780 · 10.45 Impact Factor
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    ABSTRACT: We explored the feasibility of unrelated donor haematopoietic stem cell transplant (HSCT) upfront without prior immunosuppressive therapy (IST) in paediatric idiopathic severe aplastic anaemia (SAA). This cohort was then compared to matched historical controls who had undergone first-line therapy with a matched sibling/family donor (MSD) HSCT (n = 87) or IST with horse antithymocyte globulin and ciclosporin (n = 58) or second-line therapy with unrelated donor HSCT post-failed IST (n = 24). The 2-year overall survival in the upfront cohort was 96 ± 4% compared to 91 ± 3% in the MSD controls (P = 0·30) and 94 ± 3% in the IST controls (P = 0·68) and 74 ± 9% in the unrelated donor HSCT post-IST failure controls (P = 0·02).The 2-year event-free survival in the upfront cohort was 92 ± 5% compared to 87 ± 4% in MSD controls (P = 0·37), 40 ± 7% in IST controls (P = 0·0001) and 74 ± 9% in the unrelated donor HSCT post-IST failure controls (n = 24) (P = 0·02). Outcomes for upfront-unrelated donor HSCT in paediatric idiopathic SAA were similar to MSD HSCT and superior to IST and unrelated donor HSCT post-IST failure. Front-line therapy with matched unrelated donor HSCT is a novel treatment approach and could be considered as first-line therapy in selected paediatric patients who lack a MSD. © 2015 John Wiley & Sons Ltd.
    British Journal of Haematology 07/2015; 171(4). DOI:10.1111/bjh.13614 · 4.71 Impact Factor
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    ABSTRACT: The occurrence of late sequelae after myeloablative conditioning regimens for stem-cell transplantation (SCT) has prompted the introduction of reduced-intensity chemotherapy (RIC) regimens in an attempt to reduce toxicity and spare fertility. We retrospectively evaluated gonadal function in survivors of SCT in childhood by comparing patients conditioned with a myeloablative regimen containing busulfan and cyclophosphamide (BuCy, N = 51, 28 boys) and a RIC regimen containing fludarabine and melphalan (FluMel, N = 40, 19 boys). Spontaneous puberty occurred in 56% of girls and 89% of boys after BuCy, whereas 90% of females and all males in the FluMel group entered puberty spontaneously (P = 0·012). Significantly more females (61%) conditioned with BuCy required hormone replacement compared with the FluMel group (10·5%, P = 0·012). Females in the FluMel group took significantly longer to develop elevation of serum follicle-stimulating hormone (FSH) concentrations (>10 iu/l) from the onset of puberty than females in the BuCy group (median 5·2 years vs. 2·7 years respectively, P = 0·0135). In males no difference was noted between the two conditioning groups in time to FSH elevation (median 4 years in FluMel versus 6 years in BuCy). Whilst the two regimens have similar effects on the testis, ovarian function seems to be better preserved in females undergoing SCT with RIC. © 2015 John Wiley & Sons Ltd.
    British Journal of Haematology 05/2015; 170(5). DOI:10.1111/bjh.13497 · 4.71 Impact Factor
  • O Nikolajeva · A Mijovic · D Hess · E Tatam · P Amrolia · R Chiesa · K Rao · J Silva · P Veys ·
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    ABSTRACT: Bacterial and fungal infections remain a significant cause of transplant-related mortality following allogeneic stem cell transplantation (SCT). Granulocyte transfusions (GTs) may reduce the neutropenic period after SCT and prevent further progression of the existing infection (that is, therapeutic GT) in addition to standard antibacterial and antifungal therapy. A retrospective analysis was performed on 28 consecutive pediatric SCT recipients who received at least one dose of GT between March 2003 and November 2013 at a single institution. All donors were conditioned with G-CSF+dexamethasone with harvest performed 12-18 h later. Indications for SCT were acute leukemia in 46% (13/28) and severe aplastic anemia in 21% (6/28). The main indications for GT were invasive fungal disease in 50%, bacterial infection in 21% and co-morbidities with predicted reduced tolerance to sepsis in 18% (5/28). The median number of GT was 6 (range 1-14) with a median dose of 3.56 × 10(10) granulocytes infused. The median increment in ANC was 1.06 × 10(9)/L and correlated with the granulocyte dose infused. Adverse reactions observed were mild and infrequent. Sixty-four percent of patients (18/28) are alive with only 2 of the 10 deaths being related to progression of infection. In addition there was a low overall incidence of grade 3-4 acute mucositis and a very low incidence (7%) of acute GvHD grade 3-4. Single-donor GTs afford protection to children undergoing SCT at additional risk of infection and may reduce the overall incidence of severe GvHD.Bone Marrow Transplantation advance online publication, 30 March 2015; doi:10.1038/bmt.2015.53.
    Bone marrow transplantation 03/2015; 50(6). DOI:10.1038/bmt.2015.53 · 3.57 Impact Factor
  • Sara Ghorashian · Martin Pule · Persis Amrolia ·
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    ABSTRACT: T cells can be redirected to recognize tumour antigens by genetic modification to express a chimeric antigen receptor (CAR). These consist of antibody-derived antigen-binding regions linked to T cell signalling elements. CD19 is an ideal target because it is expressed on most B cell malignancies as well as normal B cells but not on other cell types, restricting any 'on target, off tumour' toxicity to B cell depletion. Recent clinical studies involving CD19 CAR-directed T cells have shown unprecedented responses in a range of B cell malignancies, even in patients with chemorefractory relapse. Durable responses have been achieved, although the persistence of modified T cells may be limited. This therapy is not without toxicity, however. Cytokine release syndrome and neurotoxicity appear to be frequent but are treatable and reversible. CAR T cell therapy holds the promise of a tailored cellular therapy, which can form memory and be adapted to the tumour microenvironment. This review will provide a perspective on the currently available data, as well as on future developments in the field. © 2015 John Wiley & Sons Ltd.
    British Journal of Haematology 03/2015; 169(4). DOI:10.1111/bjh.13340 · 4.71 Impact Factor
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    ABSTRACT: Mutations in RMRP primarily give rise to Cartilage Hair Hypoplasia (CHH), a highly diverse skeletal disorder which can be associated with severe immunodeficiency. Increased availability of RMRP mutation screening has uncovered a number of infants with significant immunodeficiency but only mild or absent skeletal features. We surveyed the clinical and immunological phenotype of children who have undergone allogeneic haematopoietic stem cell transplantation for this condition in the UK. Thirteen patients with confirmed RMRP mutations underwent allogeneic stem cell transplantation (SCT) at two nationally commissioned centres using a variety of donors and conditioning regimens. Records were retrospectively reviewed. Median time from clinical presentation to diagnosis was 12 months (range 1 to 276 months), with three infants diagnosed with severe combined immunodeficiency (SCID) without radiographical manifestations of CHH. A total of 17 allogeneic procedures were performed on 13 patients including two stem-cell top-ups. The median age at transplant was 32.4 months (range 1.5 to 125 months). Of the eleven surviving patients, median follow-up was 50 months (range 21.6 to 168 months). RMRP mutations can cause short stature and significant immunodeficiency which can be corrected by allogeneic SCT and the diagnosis should be considered even in the absence of skeletal manifestations.
    Journal of Clinical Immunology 02/2015; 35(2). DOI:10.1007/s10875-015-0135-7 · 3.18 Impact Factor

  • Biology of Blood and Marrow Transplantation 02/2015; 21(2):S238. DOI:10.1016/j.bbmt.2014.11.367 · 3.40 Impact Factor

  • Biology of Blood and Marrow Transplantation 02/2015; 21(2):S46. DOI:10.1016/j.bbmt.2014.11.039 · 3.40 Impact Factor
  • Persis J Amrolia · Martin Pule ·

    The Lancet 10/2014; 385(9967). DOI:10.1016/S0140-6736(14)61729-3 · 45.22 Impact Factor

  • 16th Biennial Meeting of the European-Society-for-Immunodeficiencies; 10/2014
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    ABSTRACT: EBV associated post-transplant lymphoma (PTLD) is a major cause of morbidity/mortality after hematopoietic stem cell (SCT) or solid organ (SOT) transplant. Adoptive immunotherapy with EBV-specific cytotoxic lymphocytes (CTLs), whilst effective in SCT, is less successful after SOT where life-long immunosuppression therapy is necessary. We have genetically engineered EBV-CTLs to render them resistant to calcineurin inhibitor FK506 through retroviral transfer of a calcineurin A mutant (CNA12). Here we examined the ability of FK506-resistant EBV-CTLs to control EBV-driven tumour progression in the presence of immunosuppression in vivo in a xenogeneic mouse model. NOD/SCID/IL2rγ(null) mice bearing human B cell lymphoma were injected with autologous CTLs transduced either with CNA12 or eGFP in the presence/absence of FK506. Adoptive transfer of autologous CNA12-CTLs induced dramatic lymphoma regression despite the presence of FK506 whereas eGFP transduced CTLs did not. CNA12-CTLs persisted longer, homed to the tumour and expanded more than eGFP-CTLs in mice treated with FK506. Mice receiving CNA12-CTLs and treated with FK506 survived significantly longer than control treated animals. Our results demonstrate that CNA12-CTL induce regression of EBV-associated tumours in vivo despite ongoing immunosuppression. Clinical application of this novel approach may enhance the efficacy of adoptive transfer of EBV-CTL in SOT patients developing PTLD without the need for reduction in immunosuppressive therapy.
    Blood 09/2014; 124(16). DOI:10.1182/blood-2014-01-553362 · 10.45 Impact Factor
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    ABSTRACT: Severe combined immunodeficiency (SCID) can be cured by using allogeneic hematopoietic stem cell transplantation, and the absence of host immunity often obviates the need for preconditioning. Depending on the underlying genetic defect and when blocks in differentiation occur during lymphocyte ontogeny, infants with SCID have absent or greatly reduced numbers of functional T cells. Natural killer (NK) cell populations are usually absent in the SCID-X1 and Janus kinase 3 forms of SCID and greatly reduced in adenosine deaminase deficiency SCID but often present in other forms of the disorder. To determine if SCID phenotypes indicate host permissiveness to donor cell engraftment. A retrospective data analysis considered whether host NK cells influenced donor T-cell engraftment, immune reconstitution, and long-term outcomes in children who had undergone nonconditioned allogeneic stem cell transplantation between 1990 and 2011 in the United Kingdom. Detailed analysis of T- and B-cell immune reconstitution and donor chimerism was compared between the NK(+) (n = 24) and NK(-) (n = 53) forms of SCID. Overall, 77 children underwent transplantation, with survival of 90% in matched sibling donor/matched family donor transplants compared with 60% when alternative donors were used. Infants with NK(-)SCID were more likely to survive than NK(+) recipients (87% vs 62%, P < .01) and had high-level donor T-cell chimerism with superior long-term recovery of CD4 T-cell immunity. Notably, 33% of children with NK(+)SCID required additional transplantation procedures compared with only 8% of children with NK(-)SCID (P < .005). NK(-)SCID disorders are highly permissive for donor T-cell engraftment without preconditioning, whereas the presence of NK cells is a strong indicator that preparative conditioning is required for engraftment of T-cell precursors capable of supporting robust T-cell reconstitution.
    The Journal of allergy and clinical immunology 04/2014; 133(6). DOI:10.1016/j.jaci.2014.02.042 · 11.48 Impact Factor
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    ABSTRACT: Background: Although cytomegalovirus (CMV) retinitis (CMVR) is a well-recognized complication after allogeneic hematopoietic stem cell transplantation (HSCT), standard operating procedures for ophthalmic monitoring are variable. In particular, authors perceived a greater risk of CMVR after pediatric HSCT for inherited immunodeficiencies, in patients who often have pretransplantation viremia. This study was therefore performed to identify high-risk pediatric HSCT recipients who would benefit from regular ophthalmic monitoring. Methods: During a 5-year study period, we retrospectively analyzed findings in 56 of 304 consecutive HSCT recipients (age range, 0.5-197 months) in whom significant CMV viremia developed (CMV level at PCR, ≥4000 copies/mL). All HSCT recipients with significant CMV viremia underwent retinal examination weekly (inpatients) or every other week (outpatients), with examinations performed by a skilled ophthalmologist. Results: CMVR developed in 13 (4%) of 304 HSCT recipients, 23% (13 of 56) of those with significant CMV viremia. Pretransplant viremia (odds ratio, 11.3; P < .01), acute (grade ≥2) graft-vs-host disease (odds ratio, 8.2; P < .02) and mismatched graft (odds ratio, 8; P < .02) were identified as independent risk factors. Compared with other invasive CMV diseases, CMVR was more often a late-onset disease, occurring at a median of 199 days after HSCT. At diagnosis, a significantly higher CD4 T-cell count (≥200/µL; P < .03) and a lower CMV load (P < .004) was observed in children with CMVR, compared with those in whom lung, gut, or liver CMV disease developed. Conclusions: We report an increased risk of CMVR in high-risk pediatric HSCT recipients. This form of CMV disease differs from other invasive CMV disease in its relationship to immune reconstitution and viral dynamics. We have studied the relationship between these variables and suggested a risk-stratified ophthalmic screening strategy.
    Clinical Infectious Diseases 04/2014; 58(12). DOI:10.1093/cid/ciu201 · 8.89 Impact Factor

  • Biology of Blood and Marrow Transplantation 02/2014; 20(2):S89-S90. DOI:10.1016/j.bbmt.2013.12.113 · 3.40 Impact Factor
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    I Ricciardelli · J Brewin · G Lugthart · S J Albon · M Pule · P J Amrolia ·
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    ABSTRACT: Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (PTLD) remains a major cause of morbidity and mortality after hematopoietic stem cell (HSCT) or solid organ transplant (SOT). Strategies to reconstitute immunity by adoptive transfer of EBV-specific cytotoxic T lymphocyte (CTL) therapy while highly effective in the HSCT setting where immunosuppression can be withdrawn have been less successful in the SOT setting where continued immunosuppression therapy is necessary. Additionally, the complexity and time taken to generate EBV-CTLs for adoptive transfer limit the clinical applicability. We have developed a system for the rapid generation of EBV-CTLs resistant to immunosuppression based on selection of interferon-gamma (IFN-γ) secreting EBV-CTLs and retroviral transduction with a calcineurin B mutant. With this methodology, EBV-CTLs resistant to the calcineurin inhibitor Tacrolimus (TAC) can be produced in 14 days. These CTLs show high specificity for EBV with negligible alloreactivity in both proliferation and cytotoxicity assays and are able to proliferate and secrete IFN-γ in response to antigen stimulation in the presence of therapeutic doses of TAC. This strategy will substantially facilitate clinical application of this approach for the treatment of PTLD in SOT recipients.
    American Journal of Transplantation 12/2013; 13(12):3244-3252. DOI:10.1111/ajt.12475 · 5.68 Impact Factor
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    ABSTRACT: In vivo T-cell-depletion with Thymoglobulin (ATG) might contribute to the delayed immune reconstitution observed after unrelated umbilical cord blood transplantation (UCBT). We studied the impact of early, late and no ATG on immune reconstitution and outcome. 127 Children receiving UCBT in London or Utrecht were included into 3 groups: late ATG (day -5 to 0, n=48), early ATG (day -9 to -5, n= 33) and no ATG (n=46). The no ATG group received MMF+CsA as GVHD- prophylaxis, while the ATG groups both received CSA+prednisone. Endpoints studied were survival, immune-recovery, infections and GvHD. The probability of survival was similar in all groups: 71%+/-8%(no ATG), 68%+/-9%(early ATG) and 61%+/-7%(late ATG). CD3+, CD4+ and CD4+ naïve T-cell-counts were significantly higher (p<0.001) in the no ATG group at 1,2,3,6, and 12months post-UCBT. In the no ATG group significantly less viral reactivations(p=0.021) were noted. A higher probability of severe acute GvHD(31%) was found in the no ATG group compared to 18% (p =0.018) for early ATG and 5% (p<0.001) for late ATG. This was not associated with more chronic GvHD. The findings of improved immune-reconstitution, associated with lower viral reactivations, albeit at the cost of increased rates of acute GvHD (but not cGvHD), suggest that omitting ATG may be important to prevent viral reactivations.
    Blood 11/2013; 123(1). DOI:10.1182/blood-2013-05-502385 · 10.45 Impact Factor
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    H Bobby Gaspar · Waseem Qasim · E Graham Davies · Kanchan Rao · Persis J Amrolia · Paul Veys ·
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    ABSTRACT: Severe combined immunodeficiency (SCID) arises from different genetic defects associated with lymphocyte development and function and presents with severe infections. Allogeneic haematopoietic stem cell transplantation (HCT) is an extremely effective way of restoring immunity in these individuals. Numerous multi-centre studies have identified the factors determining successful outcome and survival for SCID has shown great improvement. Advances in understanding the genetic basis of disease also mean that we increasingly tailor transplant protocols to the specific SCID form. Wherever possible, we attempt to transplant SCID patients without the use of cytoreductive conditioning but it is clear that this is only successful for specific SCID forms and although survival is good, in specific patients there are ongoing humoral defects. We aim to use matched related and unrelated donors (including cord blood) whenever possible and have limited the use of mismatched haploidentical donors. The development of autologous haematopoietic stem cell gene therapy provides another treatment for the X-linked and adenosine deaminase (ADA) deficient forms of SCID, and we discuss how we have integrated gene therapy into our treatment strategy. These developments together with the advent of universal newborn screening for SCID should allow for a highly favourable outcome for this otherwise lethal condition.
    Blood 10/2013; 122(23). DOI:10.1182/blood-2013-02-380105 · 10.45 Impact Factor
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    ABSTRACT: Defective V(D)J recombination and DNA double-strand break (DSB) repair severely impair the development of T-lymphocytes and B-lymphocytes. Most patients manifest a severe combined immunodeficiency during infancy. We report 2 siblings with combined immunodeficiency (CID) and immunodysregulation caused by compound heterozygous Artemis mutations, including an exon 1-3 deletion generating a null allele, and a missense change (p.T71P). Skin fibroblasts demonstrated normal DSB repair by gamma-H2AX analysis, supporting the predicted hypomorphic nature of the p.T71P allele. In addition to these two patients, 12 patients with Artemis-deficient CID were previously reported. All had significant morbidities including recurrent infections, autoimmunity, EBV-associated lymphoma, and carcinoma despite having hypomorphic mutants with residual Artemis expression, V(D)J recombination or DSB repair capacity. Nine patients underwent stem cell transplant and six survived, while four patients who did not receive transplant died. The progressive nature of immunodeficiency and genomic instability accounts for poor survival, and early HSCT should be considered.
    Clinical Immunology 08/2013; 149(3PB):464-474. DOI:10.1016/j.clim.2013.08.006 · 3.67 Impact Factor
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    ABSTRACT: This study investigated the cognitive and psychosocial outcomes in childhood survivors of hemophagocytic lymphohistiocytosis after hematopoietic stem cell transplantation. Twenty-one children were assessed on standardized measures of cognitive and psychosocial functioning and compared with an unaffected sibling control group (n = 14). Parent and teacher reports were obtained to provide additional information. The average full-scale intelligence quotient for the patient cohort was 81 (95% CI, 72-90), which was significantly lower than both the population average of 100 (P = .001) and the average for the unaffected sibling control group (99.2, P = .002). Fifty-six percent of school-aged children were receiving additional support at school, with the majority needing high levels of support. These children also experienced significant psychosocial difficulties. Lower socioeconomic status was associated with poorer cognitive outcomes, but age at transplantation, time to transplantation, type of conditioning, and presence of mixed chimerism were not. Ten (48%) of 21 children had evidence of neurologic involvement at diagnosis, but surprisingly, this was not significantly associated with adverse neurologic outcomes, and some children who did not have any apparent neurologic involvement at diagnosis had severe learning difficulties at follow-up. In summary, childhood survivors of hemophagocytic lymphohistiocytosis are at risk of long-term cognitive and psychosocial difficulties. Prospective and systematic long-term follow-up of these patients is essential for early identification and effective management of these problems.
    The Journal of allergy and clinical immunology 08/2013; 132(4). DOI:10.1016/j.jaci.2013.05.046 · 11.48 Impact Factor
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    ABSTRACT: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare primary immune disorder defined by mutations in the syntaxin binding protein 2 (STXBP2) alias MUNC18-2. Despite defective immunity and a hyper-inflammatory state, clinical findings such as neurological, gastrointestinal, and bleeding disorders are present in a significant number of patients and suggest an impaired expression and function of STXBP2 in cells other than cytotoxic lymphocytes. We investigated four patients with FHL5 suffering from severe enteropathy and one of whom also had renal tubular dysfunction despite successful hematopoietic stem cell transplantation (HSCT). Gastrointestinal and renal biopsy specimens were analyzed by immunohistochemistry and electron microscopy. Histopathology revealed an intracytoplasmatic accumulation of PAS-positive granules and an enlarged intracytoplasmatic CD10-positive band along the apical pole of enterocytes. Electron microscopy revealed short microvilli and granules filled with electro lucent material. In addition, we described mildly dilated renal tubules and electron micrographs displayed a higher number of cytoplasmic inclusions, electrodense lysosomal and electrolucent endosomal vesicles. Mutations in STXBP2 do not only affect cytotoxic T lymphocytes but also cause changes in the intestinal and renal epithelium resulting in severe, osmotic diarrhea and renal proximal tubular dysfunction. These defects persist after successful treatment of hemophagocytic lymphohistocytosis by HSCT. Clinical manifestations in FHL5 patients despite successful HSCT may therefore be related to defective membrane trafficking in the gut and kidney. Pediatr Blood Cancer 2013; 60: 1215–1222.
    Pediatric Blood & Cancer 07/2013; 60(7). DOI:10.1002/pbc.24475 · 2.39 Impact Factor

Publication Stats

3k Citations
630.93 Total Impact Points


  • 2003-2015
    • Great Ormond Street Hospital for Children NHS Foundation Trust
      • • Department of Bone Marrow Transplant
      • • Department of Haematology and Oncology
      Londinium, England, United Kingdom
  • 2005-2014
    • University College London
      • • Institute of Child Health
      • • Molecular Immunology unit
      Londinium, England, United Kingdom
  • 2013
    • UK Department of Health
      Londinium, England, United Kingdom
  • 2006
    • Baylor College of Medicine
      • Center for Cell and Gene Therapy
      Houston, Texas, United States
  • 2001-2003
    • Imperial College London
      • • Centre for Haematology
      • • Faculty of Medicine
      London, ENG, United Kingdom