Abstract

Adenovirus, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are the three commonest causes of lethal viral disease in patients immunocompromised by allogeneic stem cell transplantation (SCT). No drugs are available to treat adenovirus or EBV infections, and conventional agents for CMV have many limitations. Hence there is considerable interest in the use of T-cell based therapies to restore immunity to these pathogens. The current application builds on this group's earlier work, showing that EBV specific CTL generated by culture of donor T cells with donor EBV-transformed lymphoblastoid cell lines (LCL) can be safely administered to SCT recipients and act as effective EBV prophylaxis. Moreover, gene marking the CTL before infusion showed that these cells persisted long term and infiltrated and destroyed sites of active EBV lymphoma. This grant now proposes to use the excellent antigen presenting properties of EBV-LCL to present additional antigens, derived from adenovirus and CMV, ultimately generating a CTL line from a single culture that has specificity for all three viruses. The three Specific Aims are based on substantial pre-clinical feasibility data.
In Aim 1, patients will continue to receive EBV-specific CTL but will receive in addition gene marked adenovirus specific CTL in a dose escalation study, to establish their safety and persistence.
In Aim 2, EBV-LCL themselves will be pulsed with adenovirus and used to generate bi-specific lines recognizing both EBV and CMV. These will be infused into patients and their persistence and anti-viral immune activity measured.
In Aim 3, EBV-LCL will be pulsed with both adenovirus and CMV, and tri-specific CTL lines prepared. Following infusion, their safety, persistence and anti-viral immune activity will be determined. This plan to develop a cell based anti-viral therapeutic that derives from a single culture system, will offer a practical and cost-effective means of preventing these three lethal infections after SCT.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA061384-08
Application #
6350143
Study Section
Virology Study Section (VR)
Project Start
1993-09-01
Project End
2003-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
8
Fiscal Year
2001
Total Cost
$355,931
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Sili, Uluhan; Leen, Ann M; Vera, Juan F et al. (2012) Production of good manufacturing practice-grade cytotoxic T lymphocytes specific for Epstein-Barr virus, cytomegalovirus and adenovirus to prevent or treat viral infections post-allogeneic hematopoietic stem cell transplant. Cytotherapy 14:7-11
Melenhorst, J Joseph; Leen, Ann M; Bollard, Catherine M et al. (2010) Allogeneic virus-specific T cells with HLA alloreactivity do not produce GVHD in human subjects. Blood 116:4700-2
Cruz, Conrad Russell; Hanley, Patrick J; Liu, Hao et al. (2010) Adverse events following infusion of T cells for adoptive immunotherapy: a 10-year experience. Cytotherapy 12:743-9
Heslop, Helen E; Slobod, Karen S; Pule, Martin A et al. (2010) Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood 115:925-35
Savoldo, Barbara; Rooney, Cliona M; Di Stasi, Antonio et al. (2007) Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-CD30zeta artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease. Blood 110:2620-30
Louis, Chrystal U; Paulino, Arnold C; Gottschalk, Stephen et al. (2007) A single institution experience with pediatric nasopharyngeal carcinoma: high incidence of toxicity associated with platinum-based chemotherapy plus IMRT. J Pediatr Hematol Oncol 29:500-5
Savoldo, Barbara; Goss, John A; Hammer, Markus M et al. (2006) Treatment of solid organ transplant recipients with autologous Epstein Barr virus-specific cytotoxic T lymphocytes (CTLs). Blood 108:2942-9
Gottschalk, Stephen; Rooney, Cliona M; Heslop, Helen E (2005) Post-transplant lymphoproliferative disorders. Annu Rev Med 56:29-44
Heslop, Helen E (2005) Biology and treatment of Epstein-Barr virus-associated non-Hodgkin lymphomas. Hematology Am Soc Hematol Educ Program :260-6
Gottschalk, Stephen; Heslop, Helen E; Rooney, Cliona M (2005) Adoptive immunotherapy for EBV-associated malignancies. Leuk Lymphoma 46:1-10

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