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Biomedical subjects

C M Bollard

Publications and source records attributed to C M Bollard.

9 recordsLinked to original sources
PubMed2005

Cytomegalovirus (CMV) infections and CMV-specific cellular immune reconstitution following reduced intensity conditioning allogeneic stem cell transplantation with Alemtuzumab.

We studied the incidence and recurrence of Cytomegalovirus (CMV) infection and reactivation in 38 recipients of Alemtuzumab reduced intensity conditioning-stem cell transplantation, and used CMV-HLA tetramer studies to discover if these events correlated with recovery of circulating CMV-specific CD8+ T cells (cytotoxic T lymphocyte (CTLs)). The cumulative incidence of CMV infection was 60% at 1 year (95% CI, 45-78%) with a median reactivation time of 24 days (range 5-95 days). All patients with CMV reactivation received Ganciclovir or Foscarnet, and only one developed CMV disease. More strikingly, only 8/21 patients had relapse of CMV antigenemia. Tetramer analysis in 13 patients showed that 11 reconstituted CMV CTLs (7/11 by day 30 and 10/11 by day 90). The development of CMV infection was accompanied by a >5-fold rise of CMV CTLs. Recurrence of CMV infection occurred only in the patients who failed to generate a CTL response to the virus. Hence, recipients of SCT using Alemtuzumab-RIC are initially profoundly immunosuppressed and have a high incidence of early CMV reactivation. However, in the majority of patients, infection is transient, and antiviral T cell reconstitution is rapid. Monitoring with CMV-specific CTLs may help identify the subset of patients at risk from recurrent infection or disease.

Adult↗
PubMed2005

Adenovirus infection rates in pediatric recipients of alternate donor allogeneic bone marrow transplants receiving either antithymocyte globulin (ATG) or alemtuzumab (Campath).

Infectious complications due to adenovirus are of increasing concern after allogeneic stem cell transplantation. Over the past 4 years, we have modified our conditioning regimens to use alemtuzumab in preference to anti-thymocyte globulin (ATG) for pediatric patients receiving stem cell transplants from alternate donors. Recent reports in adult studies implicate alemtuzumab as a risk factor for adenovirus infection. We therefore evaluated the incidence of adenovirus infection in pediatric patients receiving either ATG or alemtuzumab in their conditioning regimens. Of the 111 patients evaluated, a total of 54 patients received ATG and 57 patients received alemtuzumab. In total, 35/111 (32%) patients were infected by adenovirus, and 9/111 (8%) had adenovirus disease (AD). Adenovirus infection was greater in the alemtuzumab group than the ATG group (23/57 vs 12/54) (P=0.039) and disseminated AD was more frequent in the alemtuzumab group vs the ATG group (8/57 and 1/54 respectively) (P=0.032). The presence of Grade 3-4 graft-versus-host disease was a risk factor for adenovirus infection. Our findings highlight the fact that adenovirus infection is a frequent complication after stem cell transplantation from alternate donors in the pediatric population and that alemtuzumab increases the risk of infection compared to ATG. This work will help in identifying at-risk populations for our upcoming immunotherapy trial using adoptively transferred donor-derived adenovirus-specific cytotoxic T lymphocytes.

Adenovirus Infections, Human↗
PubMed2005

T-cell immunotherapy for adenoviral infections of stem-cell transplant recipients.

Human adenoviruses are ubiquitous lytic DNA viruses that can be divided into 51 different serotypes, grouped from A to F on the basis of genome size, composition, homology, and organization. Adenovirus infections, although frequent, are rarely fatal in immunocompetent individuals, due to potent innate and adaptive immune responses. By contrast, adenoviruses are a significant cause of morbidity and mortality in immunosuppressed individuals, for whom there are limited treatment options. Since antiviral drugs have variable efficacy in the treatment of severe adenovirus disease, iatrogenic reconstitution with in vitro expanded virus-specific cytotoxic T lymphocytes (CTLs) is an attractive option for prophylaxis and treatment, particularly because the endogenous recovery of adenovirus-specific T cells has proved important in controlling infection in vivo. Thus, we have characterized human T-cell responses to adenovirus in vitro and explored the potential of adoptive T-cell immunotherapy as a prophylactic or therapeutic strategy for adenovirus infections posttransplant.

Adenoviridae Infections↗
PubMed2001

Targeting of G(D2)-positive tumor cells by human T lymphocytes engineered to express chimeric T-cell receptor genes.

Genetic engineering of human T lymphocytes to express tumor antigen-specific chimeric immune receptors is an attractive means for providing large numbers of effector cells for adoptive immunotherapy while bypassing major mechanisms of tumor escape from immune recognition. We have applied this strategy to the targeting of a G(D2)-positive tumor, neuroblastoma, which is the commonest extracranial solid tumor of childhood. Chimeric immune receptors were generated by joining an extracellular antigen-binding domain derived from either of the 2 ganglioside G(D2)-specific antibodies sc7A4 and sc14.G2a to a cytoplasmic signaling domain. The variable domains of hybridoma antibody 14.G2a were cloned and selected using a phage display approach. Upon coincubation with G(D2)-expressing tumor cell targets, human T lymphocytes transduced with recombinant retroviruses encoding chimeric receptors based on sc14.G2a, but not sc7A4, secreted significant levels of cytokines in a pattern comparable to the cytokine response obtained by engagement of the CD3 receptor. T cells transduced with the sc14.G2a-based chimeric T-cell receptors also displayed specific lysis of G(D2)-positive neuroblastoma cells, which was blocked in the presence of monoclonal antibody 14.G2a. In the absence of nonspecific stimulation of transduced cells, their functionality declined over time and antigenic stimulation of the chimeric receptor alone did not induce commitment to proliferation. These results support the feasibility of redirecting human T lymphocytes to a tumor-associated ganglioside epitope but emphasize that successful chimeric receptor-mediated adoptive immunotherapy will require additional strategies that overcome functional inactivation of gene-modified primary T lymphocytes.

Cytokines↗
PubMed2001

Gene-marking studies of hematopoietic cells.

Gene-marking studies were the first approved clinical protocols introducing exogenous genetic material into human cells. Such studies were never intended to provide direct therapeutic benefit. Instead, they were expected to provide information about normal cell biology and disease pathogenesis that could not be obtained in any other way. However, the information gained from such studies has had a significant impact on disease management. Gene-marking studies have provided valuable insights into the biology of the human stem cell, factors that influence the efficiency of gene transfer, mechanisms of relapse after stem cell transplantation, and the pharmacodynamics of adoptive cellular immunotherapy. With continuing advances in gene-marking technology, the value of the information provided by these studies increases, thereby ensuring their continued relevance to the field of gene transfer.

Animals↗
PubMed2001

Gene therapy for paediatric leukaemia.

Improvements in the chemotherapeutic and transplant regimens have had a significant impact in improving survival rates for paediatric leukaemia. However, there are still important problems to address including what options are available for patients with chemoresistant disease and what strategies are available to avoid the concerns regarding the toxicity associated with highly cytotoxic treatment regimens. Gene therapy and immunotherapy protocols hold great promise. Using gene transfer of a marker gene, a number of biological issues in the therapy of leukaemia have been addressed. For example, by gene marking autologous bone marrow grafts it has been possible to demonstrate that infused marrow contributes to relapse in acute and chronic myeloid leukaemias. In the allogeneic transplant setting, genetically modified T-cells have proven valuable for the prophylaxis and treatment of viral diseases and may have an important role in preventing or treating disease relapse. Gene transfer is also being used to modify tumour function, enhance immunogenicity, and confer drug-resistance to normal haematopoietic stem cells. With the continued scientific advancements in this field, gene therapy will almost certainly have a major impact on the treatment of paediatric leukaemia in the future.

Cancer Vaccines↗
PubMed2000

The use of central venous catheters (portacaths) in children with haemophilia.

The experience with central venous implantable devices (portacaths) has been reviewed in children attending the Auckland Hospital Haemophilia Centre. Fourteen children had 23 portacaths inserted. Thirteen had severe Haemophilia A, of whom five had high responding inhibitors to factor VIII. All the children were HIV negative. Ages ranged from 4 months to 13 years at the time of initial placement and 12 were under 5 years. Indications for portacath placement included primary and secondary prophylaxis, induction of immune tolerance, prophylactic therapy post intracranial haemorrhage and poor venous access. Catheter-related infections occurred in 48% of cases. Staphylococcal species were the most common organisms isolated followed by gram-negative bacilli. 63% of the infections were successfully cleared with antibiotics. Haematoma formation occurred in 17% of catheters, primarily in patients who had high factor VIII inhibitor levels. Mechanical problems including blockage, leakage and extrusion of the portacath occurred less frequently (13%). The significant rate of infection in this immunocompetent population is consistent with other reports. Despite the obvious benefits of portacaths this complication is potentially serious and causes appreciable morbidity. In contrast, bleeding complication rates were relatively low.

Adolescent↗