Key Points• Human BM-MSCs can be used to successfully deliver systemic oncolytic measles virotherapy to ALL tumor targets.• This approach permits circumvention of preexisting anti-measles humoral immunity and enhanced therapeutic outcomes.Clinical trials of oncolytic attenuated measles virus (MV) are ongoing, but successful systemic delivery in immune individuals remains a major challenge. We demonstrated high-titer anti-MV antibody in 16 adults with acute lymphoblastic leukemia (ALL) following treatments including numerous immunosuppressive drugs. To resolve this challenge, human bone marrow-derived mesenchymal stromal cells (BM-MSCs) were used to efficiently deliver MV in a systemic xenograft model of precursor B-lineage-ALL. BM-MSCs were successfully loaded with MV ex vivo, and MV was amplified intracellularly, without toxicity. Live cell confocal imaging demonstrated a viral hand-off between BM-MSCs and ALL targets in the presence of antibody. In a murine model of disseminated ALL, successful MV treatment (judged by bioluminescence quantification and survival) was completely abrogated by passive immunization with high-titer human anti-MV antibody. Importantly, no such abrogation was seen in immunized mice receiving MV delivered by BM-MSCs. These data support the use of BM-MSCs as cellular carriers for MV in patients with ALL. (Blood. 2014;123(9):1327-1335) IntroductionAdult acute lymphoblastic leukemia (ALL) is an aggressive hematological malignancy with complete remission rates following initial induction therapy of 85% to 95%. [1][2][3][4][5][6][7][8] Despite cycles of combined immunosuppressive and myelosuppressive chemotherapeutics, longterm survival is achieved in fewer than half of adults, 9 and few patients with relapsed disease survive. 10 The ability to quantify and monitor minimal residual disease in the majority of patients with ALL, provides a basis-already recognized by the regulatory authorities-for early intervention with novel therapeutics prior to overt disease relapse, 11 which would be the optimal setting for novel biological therapies.Oncolytic viruses (OVs) preferentially infect and lyse transformed cells, leaving normal cells relatively unharmed. They lack crossresistance with existing therapies, and the acceptable safety profile of OVs has been demonstrated in numerous trials. [12][13][14][15][16] Vaccine-strain live, attenuated MV (MV-Edm) has shown tumor-specific replication and antitumor activity in a range of malignancies, [17][18][19][20][21][22][23][24][25][26][27][28][29][30] with published phase 1 clinical trials showing safety and some therapeutic promise in cutaneous T-cell lymphoma 31 and ovarian cancer. 32 Sophisticated manipulations of the vaccine MV genome can aid tumor targeting [33][34][35][36][37] and assist with in vivo tracking. 21,38,39 Despite this, the necessity to shield MV from neutralizing antibody during systemic delivery has not been appropriately addressed 40,41 but is likely to preclude repeat dosing regimes and impact adversely on therapy.There has been in...
BackgroundFabry disease (FD) results from X-linked inheritance of a mutation in the GLA gene, encoding for alpha galactosidase A, and is characterized by heterogeneous clinical manifestations. Two phenotypes have been described “Classic” and “late onset” which cannot be predicted exclusively by genotype. The latter has been considered an attenuated form of the disease often affecting a single organ system commonly the heart. Recent studies have demonstrated that cardiac outcomes are similar in patients with classic and late onset mutations. In this study we investigate the relationship between clinical heterogeneity and plasma lyso-Gb3 in a large single centre cohort of N215S patients and compare this to patients with other mutations.MethodsIn this single-centre, retrospective, cross-sectional study we analysed a cohort of 251 FD patients: 84 N215S mutation (37 males) and 167 non-N215S mutations (58 males). The Mainz severity score index (MSSI) was used as an index of overall disease severity. Cardiac function and morphology were assessed by electrocardiogram and echocardiogram. Left ventricular mass was calculated using the Devereux formula and the left ventricular mass index (LVMI) calculated to adjust for height (g/m2.7). The presence of white matter lesions was assessed by cerebral MRI or computed tomography (CT). GFR was measured by radio-isotope (chromium-EDTA) method and adjusted for patient height (ml/min/m2.7), and urinary protein quantification was undertaken by 24 hour urine collection. Plasma globotriaosylsphingosine (lyso-Gb3) was analysed prior to ERT in 84 patients.ResultsN215S patients showed later symptom onset (males: p< 0.0001, females: p<0.03), later development of left ventricular hypertrophy (LVH) (median survival without LVH: 41 (non-N215S) vs. 64 (N215S) years, p< 0.0001), later development of proteinuria (median survival without proteinuria 43 (non-N215S) vs 71 years (N215S), p< 0.0001), later occurrence of cerebrovascular events (stroke/ Transient Ischaemic Attacks (TIA); median survival without stroke: 74 years (non-N215S) vs. not reached (N215S), p< 0.02), later decline in renal function to GFR <60 ml/min/1.73m2 (median survival: 56 (non-N215S) vs. 72 (N215S) years, p< 0.01), and greater overall survival (median survival 81 (N215S) vs. 66 (non-N215S) years, p< 0.0006). Lyso-Gb3 was found to be less elevated in N215S compared to non-N215S male and female patients. However, the N215S population eventually reached an overall severity measured by MSSI comparable to the non-N215S without equivalent elevation of lyso-Gb3 (means: 6.7 vs. 74.3 nmol/L, p < 0.001). In addition, N215S patients showed strong correlations between lyso-Gb3 levels and LVMI, GFR, and MSSI. These associations became stronger when we investigated individuals’ life time exposure to lyso-Gb3 (calculated as [lyso-Gb3]*age): MSSI (r2 = 0.88, p< 0.0001), LVMI (r2 = 0.59, p< 0.005), and GFR (r2 = 0.75, p = 0.0001).ConclusionThese results demonstrate that the N215S mutation results in a late onset phenotype involving the heart...
Key Points• CMV serostatus significantly influences chimerism levels after T-cell-depleted allogeneic transplantation.• CMV-specific T cells are exclusively of recipient origin after R1/D2 T-cell-depleted transplants and appear to provide protective immunity.Cytomegalovirus (CMV) remains a significant cause of morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). Clinical risk varies according to a number of factors, including recipient/donor CMV serostatus. Current dogma suggests risk is greatest in seropositive recipient (R1)/seronegative donor (D2) transplants and is exacerbated by T-cell depletion. We hypothesized that in the setting of reduced-intensity T-celldepleted conditioning, recipient-derived CMV-specific T cells escaping deletion may contribute significantly to CMV-specific immunity and might therefore also influence chimerism status. We evaluated 105 recipients of alemtuzumab-based reduced-intensity HSCT and collated details on CMV infection episodes and T-cell chimerism. We used CMV-specific HLA multimers to enumerate CMV-specific T-cell numbers and select cells to assess chimerism status in a subset of R1/D2 and R1/seropositive donor patients. We show that in R1/D2 patients, CMV-specific T cells are exclusively of recipient origin, can protect against recurrent CMV infections, and significantly influence the chimerism status toward recipients. The major findings were replicated in a separate validation cohort. T-cell depletion in the R1/D2 setting may actually, therefore, foster more rapid reconstitution of protective antiviral immunity by reducing graft-vs-host directed alloreactivity and the associated elimination of the recipient T-cell compartment. Finally, conversion to donor chimerism after donor lymphocytes is associated with clinically occult transition to donor-derived immunity. (Blood. 2015;125(4):731-739)
UKALL14 (NCT01085617) randomised 655 patients aged 25-65 years with B-precursor ALL, irrespective of Philadelphia chromosome (Ph) status or cell surface CD20 expression to determine if the addition of four doses of rituximab to standard induction chemotherapy (SOC+R) resulted in improved event free survival (EFS). Patients were recruited between Dec 2010 - Jul 2017 and the primary analysis population comprises 577 patients recruited after an April 2012 amendment in which the SOC therapy was altered. The trial was powered with an 84% chance to detect a 12% improvement in EFS (Hazard ratio (HR): 0.71). Secondary endpoints included complete remission (CR), OS, non-relapse mortality, levels of minimal residual disease (MRD) after induction and relationship of response to CD20 expression. SOC consisted of daunorubicin 30mg/m2, vincristine 1.4mg/m2, dexamethasone 4 day blocks of 10mg/m2 starting d1, 8, 15 and 22. Pegylated asparaginase 1000IU/m2 was added on d4 and 18 (d18 only if >40 years) for Ph- ALL and continuous daily imatinib 600mg for Ph+ ALL. Intrathecal MTX was given on d14. Rituximab 375mg/m2 was given on d3,10,17 and 24. Two patients did not start trial treatment, both were in the SOC+R arm. Analysis is by intention-to-treat. There were 288 patients in the SOC arm and 289 in the SOC+R arm, 273 (95.5%) of whom received all 4 doses of rituximab. The arms were well-balanced for risk characteristics. Of note, 63.9% (SOC) and 62.6% (SOC+R) were aged over 40 years at randomisation and 86 patients in each arm (29.9% and 29.8%, respectively) had Ph+ ALL. CR rate, 92.7% SOC and 94.8% SOC+R, did not differ between the arms. There was no difference in the MRD response between the arms, whether assessed as positive vs. negative or as a continuous variable; 121 (42.2%) of patients were MRD negative at induction completion in the SOC arm vs. 120 (41.8%) in the SOC+R arm. Likewise, the rate of severe/adverse events and non-relapse mortality did not differ between arms. At a median follow-up of 50.5 months (7 days - 83.6 months), 3 year EFS for SOC is 41.9% (95% CI: 35.8 - 48.0) versus SOC+R 48.7% (42.4 - 54.8), Hazard Ratio(HR) 0.88 (0.71 - 1.11), p=0.28, see figure1a. Pre-planned subgroup analyses by cytogenetic ("high risk" was defined as t(9;22), t(4;11), low hypodiploidy/near triploidy and complex karyotype) and other risk groups (age, presenting WBC) as well as by cell surface CD20 expression did not reveal any significant interactions. However, we did find that % blasts expressing CD20 was an independent poor prognostic factor; Youden's cut-off, to determine the best cut-off for a continuous variable, suggested a % CD20 expression of 11.7% as the optimal cut-off. EFS HR for 10-20% CD20 was 1.74 (0.98-3.10) and >20% was 2.20 (1.27 - 3.81), compared to <10% CD20. Outcomes were also analysed by post-induction treatment assignment; myeloablative allogeneic stem cell transplant (MAalloSCT) was assigned for patients with high risk ALL aged 40 and under with suitable donor, reduced intensity-conditioned RICalloSCT was evaluated, as part of the trial, in all patients over 40 years, with suitable donor and consolidation/maintenance was assigned to standard risk/no suitable donor. Of note, there was a large and statistically significant benefit to SOC+R among those who received MAalloSCT, SOC N= 53, 3 year EFS 50.7% (35.9 - 63.7) vs. SOC+R, N=40, 3-year EFS 72.2% (54.9 - 84.2), HR 0.47 (0.23 - 0.95), p=0.03 (figure 1b) which was not evident in the RICalloSCT or maintenance groups and related to a reduction in relapse risk. Among those who received MAalloSCT, SOC and SOC+R, the arms were not totally balanced, with a greater preponderance of high-risk genetics in the SOC+R arm: 29 (64.4%) SOC versus 28 (77.8%) SOC+R, suggesting that the benefit of SOC+R combined with MAalloSCT was able to outweigh some of the adverse genetic risk. By contrast to the GRAALL-2005/R study, in which rituximab was given during all treatment phases, for a total of 16 to 18 infusions, we did not find an overall statistically significant benefit for 4 infusions of rituximab during induction. The non-significant trend to a better outcome with SOC+R underscores the necessity for including 16-18 doses of rituximab to obtain the full benefit. However, our trial shows no treatment interaction of SOC+R with Ph+ status or CD20+ expression level, suggesting that the GRAALL-2005/R results may possibly be generalizable to all patients with B-precursor ALL. Disclosures Rowntree: Novartis: Consultancy. McMillan:Sandoz: Honoraria; Pfizer: Honoraria, Research Funding; BMS: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Gilead: Honoraria; Celgene: Honoraria, Speakers Bureau; Novartis: Honoraria; MSD: Honoraria. Menne:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau. Fielding:Amgen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy. OffLabel Disclosure: Rituximab - the agent to which patients were randomised during this study
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