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Biomedical subjects

Stephen Mackinnon

Publications and source records attributed to Stephen Mackinnon.

At least 37 records · Page 2Linked to original sources
PubMed2004

Incidence and outcome of adenovirus disease in transplant recipients after reduced-intensity conditioning with alemtuzumab.

Adenoviruses are emerging as a major cause of infectious complications after allogeneic transplantation. We evaluated the incidence and outcome of symptomatic adenovirus infection or adenovirus disease after alemtuzumab-based reduced-intensity conditioning in 86 consecutive patients. The overall probability of adenovirus disease was 18.4% (11/86 patients). Five patients died of progressive adenovirus disease, and this was the most important infectious cause of mortality in this cohort. The probability of nonrelapse mortality was 49% in patients with adenovirus disease compared with 25.5% in those without (P=.007). The severity of lymphocytopenia and continuation of immunosuppressive therapy were the most important risk factors for progressive adenovirus disease and death. In contrast, patients who were not receiving immunosuppressive therapy or had had it reduced or withdrawn cleared the virus. We also detected a correlation between the lack of preemptive anti-cytomegalovirus (CMV) therapy for CMV reactivation and the risk of progressive adenovirus disease (P=.05). Our findings highlight the emergence of adenovirus as an important posttransplantation pathogen even after reduced-intensity conditioning and demonstrate the effect of the severity of lymphocytopenia, anti-CMV prophylaxis, and immunosuppressive therapy on the outcome of adenovirus disease.

Adenoviridae Infections↗
PubMed2004

Cytomegalovirus: the role of CMV post-haematopoietic stem cell transplantation.

Human cytomegalovirus (HCMV) is a large DNA virus that is well equipped to evade host immune responses and able to establish lifelong latency. It is able to modulate both innate and adaptive immune reactivity, and has multiple effects on the cell cycle and apoptosis. It is a major opportunistic pathogen in immunocompromised hosts. Reactivation of latent virus may re-stimulate memory T-cell responses that are sufficient to re-establish control over viral replication if the degree of immune suppression is not too great. Following allogeneic transplantation immune responses are often inadequate resulting in progressive tissue damage manifesting as over HCMV disease that usually presents as pneumonitis, colitis or hepatitis. Currently available antiviral pharmacotherapies are limited by toxicities and lack of efficacy in established HCMV disease. Efforts have therefore focused on molecular diagnostic surveillance protocols that allow earlier intervention, and the development of adoptive immunotherapeutic strategies to hasten host immune reconstruction.

Cytomegalovirus↗
PubMed2004

Augmentation of virus-specific immunity after hematopoietic stem cell transplantation by adoptive T-cell therapy.

Adoptive transfer of virus-specific T cells offers the potential for accelerating reconstitution of antigen-specific immunity after allogeneic hematopoietic stem cell transplantation. However, the logistics of producing virus-specific T cells and the risk of inducing graft-versus-host disease has limited their application. We developed a relatively simple system employing cytomegalovirus lysate-pulsed, monocyte-derived dendritic cells as stimulator cells, requiring only a single blood draw from the donor. We treated 16 patients with these T-cell lines, administered after the detection of human cytomegalovirus (HCMV) DNA by polymerase chain reaction. Massive in vivo expansions of HCMV-specific cytotoxic T lymphocytes (3-5 log) were observed within days of adoptive transfer. In eight cases viral titers were decreasing within 5 days and antiviral drug therapy was not required. The T-cell receptor CDR3 lengths of HCMV-specific cytotoxic T lymphocytes expanding in vivo were identical to those of the transferred cells. A low incidence of late CMV reactivation was seen (2/14 assessable patients compared with 45/72 historical controls, p = 0.001) and no significant toxicities were observed. Our findings indicate that application of cell lines generated in relatively short-term in vitro cultures is both feasible and effective in a clinical environment. This simple in vitro methodology should allow widespread application of adoptive transfer of virus-specific T cells.

Adoptive Transfer↗
PubMed2003

Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines.

Adoptive transfer of CMV-specific T cells offers the potential for reconstitution of viral immunity after allogeneic transplantation. However, the logistics of producing virus-specific T-cell clones has limited the application of cellular therapies. We treated 16 patients for CMV infection with polyclonal CMV-specific T-cell lines generated by short-term culture. Massive in-vivo expansions of CMV-specific cytotoxic T lymphocytes were observed, resulting in reconstitution of viral immunity. In eight cases antiviral drugs were not required, and subsequent episodes of reactivation occurred in only two patients. Our findings indicate that application of CMV-specific cell lines is both feasible and effective in a clinical environment.

Adoptive Transfer↗
PubMed2003

Dose-escalated donor lymphocyte infusions following reduced intensity transplantation: toxicity, chimerism, and disease responses.

Data on the application of donor lymphocyte infusions (DLIs) following reduced-intensity transplantation (RIT) remain limited. Persistence of host antigen-presenting cells might increase the efficacy or toxicity of cellular immunotherapies. We report the results of dose-escalating DLIs in 46 patients undergoing RIT, who received a total of 109 infusions to treat mixed chimerism or residual or progressive disease. Diagnoses were myeloma (n = 19), Hodgkin lymphoma (n = 13), non-Hodgkin lymphoma (n = 10), and other (n = 4). Thirty-two had an HLA-matched family donor and 14 an unrelated donor. Grades II to IV graft-versus-host disease (GVHD) occurred in 5 sibling and 7 unrelated donor recipients. GVHD was more common (P =.002), occurred at lower T-cell doses, and was more severe in the unrelated donor cohort. Conversion from mixed to multilineage full donor chimerism occurred in 30 of 35 evaluable patients. Presence of mixed chimerism in the granulocyte lineage at the time of DLI did not predict for chimerism response or GVHD. Disease responses occurred in 63% of patients with myeloma and 70% of those with Hodgkin lymphoma and were not predicted by changes in chimerism. These data support the presence of clinically relevant graft-versus-Hodgkin activity and indicate that DLI may be associated with a significantly increased toxicity in unrelated compared to sibling donor transplant recipients receiving identical treatment protocols.

Adult↗
PubMed2003

Reconstitution of the Epstein-Barr virus-specific cytotoxic T-lymphocyte response following T-cell-depleted myeloablative and nonmyeloablative allogeneic stem cell transplantation.

The recovery of circulating antigen-specific T-cell immunity to Epstein-Barr virus (EBV) was determined in ELIspot assays following allogeneic myeloablative or nonmyeloablative stem cell transplantation (MST/NST). In 8 of 12 MST patients receiving an alemtuzumab-treated graft, the frequency of the EBV-specific reactivities was similar to or greater than that seen in the healthy controls. A response was detectable in 3 of 6 and 6 of 9 patients by 3 and 6 months, respectively, and in all patients by one year following MST. In contrast, only 1 of 9 (95% confidence interval [CI], 0-2.8) patients made a detectable EBV-specific response by 6 months following NST conditioned with fludarabine, melphalan, and alemtuzumab. Responses were detected in 7 of 10 patients by 1 year after NST. Parallel surveillance demonstrated that other virus infections occurred more frequently and earlier after transplantation in NST patients. The use of alemtuzumab in vivo in the nonmyeloablative conditioning might have resulted in the delay in EBV-specific T-cell recovery and increased virus infections.

Alemtuzumab↗
PubMed2003

Pharmacokinetics of alemtuzumab used for in vivo and in vitro T-cell depletion in allogeneic transplantations: relevance for early adoptive immunotherapy and infectious complications.

Persistence of alemtuzumab at lympholytic concentrations after reduced-intensity conditioning allogeneic stem cell transplantations (RITs) could impair immune reconstitution and reduce donor T-cell-mediated graft-versus-leukemia/lymphoma (GVL) effects, derived from the graft or subsequent adoptive immunotherapy. We have studied the pharmacokinetics of alemtuzumab in 2 different groups: RIT (100 mg alemtuzumab in vivo over 5 days) and myeloablative allografts (20 mg alemtuzumab added in vitro to the stem cells prior to return). Alemtuzumab concentrations in RIT patients were in excess of that required to kill infused donor CD52+ cells at the time of transplantation and remained at potentially lympholytic levels (> 0.1 microg/mL) for approximately 56 days after transplantation, 26 days longer than for the myeloablative group. Total lymphocyte counts were significantly lower in the RIT group persisting beyond 6 months after transplantation (P =.005), and median absolute CD4 counts higher than 200 x 106/L were delayed until 9 months after transplantation.

Adolescent↗
PubMed2003

Development and clinical application of a fully controlled quantitative PCR assay for cell-free cytomegalovirus in human plasma.

BACKGROUND: Cytomegalovirus (HCMV) disease continues to be a major problem in certain patient groups, including bone marrow transplant (BMT) recipients. The quantification of HCMV genome is clinically useful for the diagnosis of HCMV disease, for the virological surveillance of high-risk patients and for monitoring antiviral therapy. OBJECTIVES: To develop a novel, robust, and fully controlled PCR (qPCR) for the quantification of HCMV DNA in plasma samples and to demonstrate its clinical usefulness in the BMT setting. STUDY DESIGN: The newly developed HCMV qPCR employs cell culture-derived murine CMV as an internal control for both extraction and amplification. Following amplification using common primers, detection of both internal control and patient HCMV amplicons is by specific probes and a chemiluminescence microtitre plate system. Its performance was evaluated using the routine non-quantitative nested HCMV PCR on whole blood (NQPCR) and correlated with clinical events such as disease and antiviral therapy. RESULTS: A high level of concordance (85.1%) was found between the novel assay and the NQPCR, with the qPCR being slightly more sensitive. The samples giving discordant results generally had levels of HCMV DNA close to the limit of detectability or had been stored for prolonged periods. CONCLUSIONS: The use of plasma as an analyte by the newly developed assay avoids the detection of cell-associated virus. On the other hand, testing a comparatively large volume of plasma ensures that sensitivity is not compromised by not detecting cell-associated HCMV. In a small preliminary evaluation in BMT recipients, changes in HCMV 'viral load' correlated with initiation and discontinuation of antiviral therapy and were biologically plausible.

Base Sequence↗
PubMed2003

Assessing diversity: immune reconstitution and T-cell receptor BV spectratype analysis following stem cell transplantation.

T-cell receptor (TCR) BV spectratyping provides information concerning immune reconstitution complementary to that derived from monoclonal antibody analysis of surface antigen expression. However, the most appropriate way to analyse and represent these data, the number of subfamilies that should be analysed, and the effects of CD4/8 ratio on observed diversity, remain unclear. A diversity scoring system was developed based on analysis of 11 cord blood (CB) and 12 normal adult BV spectratypes. CB subfamily spectratypes demonstrated minor deviations from a Gaussian pattern consistent with current knowledge about germline TCR rearrangements. Diversity scores were significantly lower in myeloma patients than normal adults (P < 0.001) and fell significantly following stem cell transplantation (P = 0.003). Subsequently increasing diversity was not detected by two previously described complexity scoring systems. The CD4/8 ratio was neither the major determinant of the absolute diversity score nor of the change in score for individual patients, suggesting that analysis of unselected mononuclear cells can provide information largely independent of CD4/8 ratios. There was a relatively low correlation between individual subfamily scores and overall diversity score. The novel and objective diversity scoring system described appears better able to document changes in spectratype patterns than previously described techniques and should aid the standardization of reporting.

Adult↗
PubMed2003

T- and B-cell immune reconstitution and clinical outcome in patients with multiple myeloma receiving T-cell-depleted, reduced-intensity allogeneic stem cell transplantation with an alemtuzumab-containing conditioning regimen followed by escalated donor lymphocyte infusions.

Immune reconstitution after conventional allogeneic transplantation is a major determinant of survival. We conducted a detailed investigation of T- and B-cell immune reconstitution and clinical outcome in 19 patients with multiple myeloma undergoing reduced-intensity stem cell transplantation using in vivo T-cell depletion with alemtuzumab. These patients experienced delayed T-cell recovery, particularly in the naïve (CD45 RA+) CD4 compartment. T-cell receptor spectratype analysis showed a reduced repertoire diversity, which improved rapidly after the administration of donor leucocyte infusions and subsequent conversion to full donor T-cell chimaerism. Post-transplant recovery of CD19+ B cells was also delayed for up to 18 months. Spectratype analysis of IgH CDR3 repertoire revealed a gradual normalization in IgM spectratype complexity by 6-12 months after transplant. There was a high incidence of viral infection, particularly cytomegalovirus reactivation, but the regimen-related mortality was low, perhaps because of the very low incidence of acute graft-versus-host disease (GVHD; grade I-II skin GVHD was seen in 5/19 patients). Over 80% of all patients have relapsed at a median of 283 (range 153-895) d after transplant, suggesting that the initially low rate of GVHD comes at a high price with regard to the desired graft-versus-myeloma effect.

Adult↗
PubMed2003

Reduced-intensity transplantation with in vivo T-cell depletion and adjuvant dose-escalating donor lymphocyte infusions for chemotherapy-sensitive myeloma: limited efficacy of graft-versus-tumor activity.

Reduced-intensity conditioning regimens allow application of allogeneic stem cell transplantation to greater numbers of patients with myeloma by reducing transplantation-related mortality. We prospectively evaluated the role of an approach incorporating in vivo T-cell depletion and subsequent adjuvant donor lymphocyte infusions (DLIs) as part of front-line therapy for chemotherapy-sensitive multiple myeloma. Twenty patients with HLA-matched related (n = 12) or unrelated (n = 8) donors entered the study. None had previously undergone autologous transplantation. Acute graft-versus-host disease (GVHD) following transplantation was minimal (3 grade II and no grade III or IV). Nonrelapse mortality rate was relatively low (15%) compared with conventional myeloablative allogeneic transplantation series, although it remained significantly higher than in the autologous setting. Disease responses by 6 months posttransplantation were modest (2 in complete remission, 4 in partial remission, 2 were minimally responsive, 6 had no change, 3 had progressive disease, and 3 were not evaluable). Fourteen patients received escalating-dose DLI for residual/progressive disease. Three developed acute GVHD and 2 developed limited chronic GVHD. Seven demonstrated further disease responses, which appeared to be more common in those developing GVHD (5 of 5 versus 2 of 9; P =.02). All responses were associated with conversion from mixed to full donor T-cell chimerism. Response durations were disappointing (5 <12 months) and progression often occurred despite persisting full donor chimerism. Two-year estimated overall survival and current progression-free survival rates (intention to treat with DLI from 6 months) were 71% and 30%, respectively. The current approach incorporating T-cell depletion appears excessively immunosuppressive despite attempts to restore immune function with DLI. Dose escalation failed to allow convincing dissociation of graft-versus-myeloma from GVHD. Attempts to hasten immune reconstitution and to focus and amplify appropriate components of allogeneic T-cell responses will be required to increase complete remission rates and response durations.

Adult↗
PubMed2003

Reconstitution of T-cell repertoire after autologous stem cell transplantation: influence of CD34 selection and cytomegalovirus infection.

The period of immunodeficiency following autologous hematopoietic stem cell transplantation is characterized by transient expansions of CD8+CD45RO+CD57+ T lymphocytes, displaying markers of an activated phenotype. Most evidence suggests that this early reconstitution results from proliferation of mature T cells that have survived conditioning or were transferred with the graft. Although homeostatic mechanisms are thought to act in maintaining total T-cell numbers, the degree to which antigen-driven expansions contribute and the nature of the stimulating antigens remain unclear. CD34 selection of stem cell grafts reduces the available T-cell pool, potentially delaying immune reconstitution and resulting in increased infective complications. In the allogeneic transplantation setting, lymphopenia has been associated with cytomegalovirus (CMV) infection risk and, if persistent, with adverse outcome. We prospectively studied patients undergoing CD34-selected (n = 13) or unselected (n = 13) autologous hematopoeitic stem cell transplantation for immune reconstitution and CMV infection. No significant differences were demonstrated between graft types with respect to lymphocyte subset recovery, T-cell receptor beta-chain variable region spectratype diversity, or CMV DNA detection rates (45% versus 40%). CMV infection was associated with a trend toward higher rather than lower CD8+ counts at 6 weeks posttransplantation (P =.08) that became significant by 3 months (P=.007), and that was associated with decreased T-cell receptor beta-chain variable region spectratype diversity (P =.01). CMV-specific HLA-tetramer analysis demonstrated transient expansions with CDR3 lengths corresponding to those of some of the major posttransplantation T-cell expansions demonstrated by spectratype analysis suggesting that CMV-specific T cells contribute to the pattern of immune reconstitution.

Adult↗
PubMed2003

Allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning in acute lymphoblastic leukemia: a feasibility study.

BACKGROUND AND OBJECTIVES: Numerous studies have reported the feasibility of performing allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning, although results in individual diseases are scarce, with no studies in patients with acute lymphoblastic leukemia (ALL). We sought to analyze the results of reduced intensity conditioning for allografts in adult patients with ALL. DESIGN AND METHODS: We report the results of a reduced intensity conditioning regimen followed by allogeneic hematopoietic stem cell transplantation in 27 adult patients with high-risk ALL who were included in four prospective studies. RESULTS: The median age was 50 years; 23 (85%) patients were beyond first complete remission, 44% were chemorefractory and 41% were Philadelphia chromosome positive. Donors were mismatched related donors or volunteer unrelated donors in 12 cases (44%). The incidence of grades II-IV acute graft-versus-host disease (GVHD) was 48%, and 13 of 18 evaluable patients (72%) developed chronic GVHD. Currently nine patients are alive, with a median follow-up of 809 days (range, 381-1375). The 2-year incidence of transplant-related mortality was 23% (95% CI, 11% to 46%), and the 2-year probability of overall survival was 31% (95% CI, 12 to 48%), while the 2-year incidence of disease progression was 49% (95% CI, 33% to 72%). The 2-year incidence of disease progression in patients with and without GVHD was 35% (95% CI, 19% to 57%) and 70% (95% CI, 47% to 100%), respectively (p=0.05). INTERPRETATION AND CONCLUSIONS: This retrospective study suggests that allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning might be a useful therapeutic option for some patients with ALL who are ineligible for standard myeloablative conditioning. However, this treatment modality needs to be evaluated in prospective trials, and should not be employed outside clinical studies.

Adolescent↗
PubMed2002

Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders.

Although nonmyeloablative conditioning regimen transplantations (NMTs) induce engraftment of allogeneic stem cells with a low spectrum of toxicity, graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality. In vivo T-cell depletion, using alemtuzumab, has been shown to reduce the incidence of GVHD. However, this type of maneuver, although reducing GVHD, may have an adverse impact on disease response, because NMTs exhibit their antitumor activity by relying on a graft-versus-malignancy effect. To explore the efficacy of alemtuzumab compared with methotrexate (MTX) for GVHD prophylaxis, we have compared the results in 129 recipients of a sibling NMT enrolled in 2 prospective studies for chronic lymphoproliferative disorders. Both NMTs were based on the same combination of fludarabine and melphalan, but the United Kingdom regimen (group A) used cyclosporin A plus alemtuzumab, whereas the Spanish regimen (group B) used cyclosporin A plus MTX for GVHD prophylaxis. Patients receiving alemtuzumab had a higher incidence of cytomegalovirus (CMV) reactivation (85% versus 24%, P <.001) and a significantly lower incidence of acute GVHD (21.7% versus 45.1%, P =.006) and chronic GVHD (5% versus 66.7%, P <.001). Twenty-one percent of patients in group A and 67.5% in group B had complete or partial responses 3 months after transplantation (P <.001). Eighteen patients in group A received donor lymphocyte infusions (DLIs) to achieve disease control. At last follow-up there was no difference in disease status between the groups with 71% versus 67.5% (P =.43) of patients showing complete or partial responses in groups A and B, respectively. No significant differences were observed in event-free or overall survival between the 2 groups. In conclusion, alemtuzumab significantly reduced GVHD but its use was associated with a higher incidence of CMV reactivation. Patients receiving alemtuzumab often required DLIs to achieve similar tumor control but the incidence of GVHD was not significantly increased after DLI.

Adult↗