H E Heslop

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..Major challenges remain for defining indications for preemptive therapies and integrating novel and conventional therapies...

..In conclusion, recipients of alternative donor transplants at our institution have significantly delayed adv-specific cellular immune recovery, which correlates to an increased risk of adv-associated morbidity and mortality...

..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...

..In a number of settings, gene modified tumor vaccines, cytotoxic T cells and dendritic cells are producing both immunomodulation and clinically evident benefits. Continued exploration of this approach seems well justified...

..Hence, recombinant adenoviruses encoding LMP2A effectively transduce DCs and direct the generation of LMP2A-specific CTLs. This approach will be a potent strategy in Hodgkin's lymphoma immunotherapy...

..In summary, this strategy safely increases the anti-lymphoma/leukemia effects of CAR.19-redirected T lymphocytes and may be a useful approach for treatment of patients with B-cell malignancies...

..This work will help in identifying at-risk populations for our upcoming immunotherapy trial using adoptively transferred donor-derived adenovirus-specific cytotoxic T lymphocytes...

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..We are now studying other virally-linked malignancies to discover whether a similar approach will be of therapeutic value...

..Hence, RISCT using lymphodepleting antibodies may be of value for older patients with AML, even in those with active or high-risk disease, and even if they lack an MHC-identical sibling donor...

..Given this high incidence of HHV-6 and the possibility of successful outcome with prompt treatment, a high index of suspicion of this disorder is required in recipients of monoclonal antibody supported allografts...

..Strategies on how to improve the antitumor activity of EBV-specific CTL are being discussed. If effective, these strategies will have broad implications for T cell therapies for a range of human tumors with defined antigens...

..At present, most measures to assess IHJ are complex, insensitive and may be subject to IHJ selection bias inherent to the technology used...

..For children undergoing stem cell transplantation (SCT) from alternative donors, alemtuzumab with a myeloablative conditioning regimen resulted in DFS comparable to MSD...

..CI of HHV-6 may confound the interpretation of HHV-6 viremia after stem cell transplantation; consideration of the possibility of CI HHV-6 will avoid unnecessary antiviral therapy...

..Our data show encouraging outcomes for patients with chemosensitive relapsed HL who receive hematopoietic stem cell transplant (HSCT) and support the value of the procedure even when the disease is chemoresistant...

..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...

..Hence, malignant B cells with a primary drug-resistant phenotype can be targeted by T- cell-mediated effector activity after immunization of human subjects...

..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...

..We conclude that, for children with SAA, AD transplantation is as effective as MSD transplantation. Further, compared with ATG, preparatory regimens containing Campath may be associated with a lower incidence of extensive, chronic GHVD...

..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...

..Future clinical studies will test the efficacy of CTL with improved antigen-specificity and resistance to Hodgkin immune evasion strategies...

..Some of these approaches are now being evaluated in clinical trials...

..The ability of Ad5/F35 to deliver transgenes to primitive HPC with high efficiency and low toxicity in the absence of growth factors provides an improved means of studying the consequences of transient gene expression in these cells...

..A number of strategies to genetically modify the infused T cells and modulate the host environment are under evaluation...

..In contrast, delivery of nontransduced T cells did not change the tumor growth pattern. Adoptive transfer of HER2-specific T cells may represent a promising immunotherapeutic approach for medulloblastoma...

..Current efforts are focused on providing protection toward a broader range of viruses safely, rapidly and effectively...

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..We have demonstrated the clinical feasibility of this approach after haploidentical transplantation by scaling up production using clinical grade materials...

..We found that the incorporation of an inducible caspase-9 suicide gene allowed efficient elimination of transgenic CTLs after exposure to a chemical inducer of dimerization, thereby increasing the safety and feasibility of the approach...

..By simultaneously expanding a portion of the selected product, we can characterize phenotype and function of the infused product and link them with subsequent in vivo outcome...

..Lymphodepleting mAbs prior CTL transfer may represent an alternative to chemotherapy to enhance expansion of infused CTL. This study is registered at (http://www.clinialtrials.gov) as NCT00608257...

..This trial was registered at www.clinicaltrials.gov as #NCT00590083...

..Hence, quantitative measurement of EBV DNA may best be used to enable the prompt rather than the preemptive treatment of PTLD...

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..In a retrospective study, we compared allogeneic PBSCT (n = 30) with BMT (n = 110) in children with acute leukemia between January 2001 and September 2006...

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..More studies using larger and randomized controlled trials are needed to confirm the long-term cost-effectiveness of each procedure...

..This study is registered at http://www.cancer.gov/clinicaltrials (protocol IDs: BCM-H-9936, NCT00062868, NCT00070226)...

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..Thus, the regimen that we describe can be used with minimal toxicity to effectively overcome graft failure after myeloablative HSCT in children...

..We believe that this approach will become of increasing value as clinical applications for MSCs develop further...

..The infusion of EBV-CTL has been demonstrated to be safe and effective in allogeneic HSCT recipients and their use post-SOT is being evaluated...

..This approach may prove beneficial for patients with high-risk B-ALL who have recently received an HSC or CB transplant and are at risk of infection and relapse...

..These results demonstrate that administration of EBV-specific CTLs to patients with advanced NPC is feasible, appears to be safe, and can be associated with significant antitumor activity...

..The use of genetically modified T cells or newer suicide genes may result in improved safety and efficacy. Current challenges are to define indications for immunotherapy or antibody therapy in patients with incipient or overt PTLD...

..Rituximab effectively induced regression of PTLD in OLT recipients. However, EBV-specific T-cell immunocompetence, which may be crucial for the long-term control of EBV-mediated proliferation, did not improve...

..Amyotrophic lateral sclerosis (ALS), an inexorably progressive motoneuron disease, is accompanied by significantly increased markers of inflammation. These inflammatory constituents could protect, harm, do neither, or do both...

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..Ad5F/K21 and Ad5F/RGD should be of value for the genetic modification of human primary leukemia cells...

..This approach may be of value in patients affected by HL...

..A major remaining challenge is to assess the significance of an elevated EBV load posttransplantation and to determine the indications for preemptive treatment...

..These data are consistent with an expansion and persistence of adoptively transferred EBV-CTLs that is limited in the presence of continued immunosuppression but that nonetheless produces clinically useful antiviral activity...

..One additional patient had a partial response, and five had stable disease. The performance and fate of these human tumor antigen-specific T cells in vivo suggests that they might be of value for the treatment of EBV+ Hodgkin lymphoma...

..To overcome these immune evasion strategies a number of approaches have been developed including targeting CTL to subdominant EBV antigens and genetically modifying CTL to increase their potency...

..Current research focuses on defining the optimum type of cell for transfer, genetically modifying infused T cells to augment function and overcome tumor evasion strategies and modulating the host environment...

..This approach is being used in a current clinical trial...

..The use of genetically modified T cells or the use of newer suicide genes may result in improved safety and efficacy...

..TGF-beta-resistant CTL had a functional advantage over unmodified CTL in the presence of TGF-beta-secreting EBV-positive lymphoma, and had enhanced antitumor activity, supporting the potential value of this countermeasure...

..05). These findings illustrate that frequent EBV viral load monitoring and preemptive immunosuppression modulation have an integral role in preventing PTLD in the pediatric liver transplant population...

..If these strategies to improve the therapeutic potential of immunotherapy for EBV-associated tumors prove successful, this type of treatment may be adapted to other tumors expressing known (viral) antigens...

..Monoculture-derived multispecific CTL infusion could provide a safe and efficient means to restore virus-specific immunity in the immunocompromised host...

..The in vivo myeloreductive and lymphoreductive properties of lytic CD45 MAb in humans, therefore, closely parallel the activity seen in a murine model and, therefore, may be of similar value...

..Relapse remains the major cause of transplant failure and immunotherapy strategies post-transplant to augment the graft versus leukaemia effect are being explored...

..The presence of viral genomes in these lymphomas, however, offers targets for intervention and approaches under evaluation include adoptive immunotherapy, interferon, and small molecules targeting aspects of virus biology...

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..Herein we describe the use of cytokine polymorphisms and real-time quantitative polymerase chain reaction (qPCR) Epstein-Barr virus (EBV) viral load to identify patients at risk for PTLD development...

..Tumor-specific, Flexi-IL12-transduced EBV-specific CTL should have a functional advantage over unmodified CTL, particularly in the presence of the adverse Th2 cytokine environment produced by Hodgkin tumor cells...

..This bioprocess optimization increased T-cell output while decreasing the complexity and cost of CTL manufacture, making cell therapy more accessible...

..This study is registered at www.clinicaltrials.gov as NCT00078533...

..Despite these advances, it remains a major challenge to define indications for preemptive therapies for PTLD and to integrate novel therapeutic approaches with conventional therapies...

..A number of approaches to overcome these tumor evasion strategies including targeting CTLs to the expressed antigens and genetic modification of CTLs are being evaluated...

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..These new LMP2 epitopes broaden the diversity of HLA alleles with available epitopes, and, in particular, those epitopes conserved between EBV strains provide valuable tools for immunotherapy and immune monitoring...

..Genetic modification of T cells with CARs specific for target antigens, expressed at too low a level to be effectively recognized by monoclonal antibodies, may allow immunotherapy to be more broadly applicable for human cancer therapy...

..As there is a wide differential diagnosis for pulmonary infiltrates developing post transplant, TRALI may be under-recognized and should be considered in this setting...

..If effective, such strategies could be applied not only to other EBV-associated malignancies, but also to a broad range of human tumors with defined tumor antigens and similar immune evasion strategies...

..These pre-clinical and clinical results warrant further evaluation of anti-CD45 MAbs in subablative preparative regimens for stem cell transplantation...

..In addition, our method for selecting EBV-specific CTL from naive individuals by precursor cell enrichment may be applicable to the immunotherapy of cancer patients with a low frequency of tumor- or virus-specific CTL...

..Because measurement of EBV DNA load as a single parameter has a poor positive predictive value for development of PTLD, the association of these assays may be of help in the identification of patients at risk for PTLD...

..This approach may be worthy of further study, particularly in patients with a high risk of relapse...

..We review possible factors contributing to the development of this syndrome in these three patients...

..Third, inducible caspase 9 maintains function in T cells overexpressing antiapoptotic molecules. These characteristics favor incorporation of inducible caspase 9 as a safety feature in human T-cell therapies...

..Tumor-specific CTLs expressing HATGF-betaRII-Deltacyt should have a selective functional and survival advantage over unmodified CTLs in the presence of TGF-beta-secreting tumors and may be of value in treatment of these diseases...

..Targeting LMP1 in these malignancies may improve the efficacy of current adoptive immunotherapy approaches...

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..Taken together, these program elements especially the mentored laboratory research experience, should provide trainees with a strong foundation for translational research careers in cell and gene therapy. ..