Improved Retroviral Gene Therapy in AIDS Lymphoma

Zaia, John A.

Abstract

Project V will evaluate HIV vector-mediated delivery of anti-HIV ribozyme genes into stem cells, followed by autologous stem cell transplantation (ASCT) for the treatment of AIDS lymphoma. This project will specifically address the issue of safety in HIV-vector application using novel methods for vector modification and production. In addition, improved assays for detecting helper-virus contamination in vector preparations will be established. For gene therapy-based ASCT in AIDS lymphoma patients, this project will develop anti-HIV-1 ribozymes designed for use not only for the improvement of safe vector production, but also for eventual anti-viral effect in the clinical study. The study of the HIV vector and the efficacy of the anti-HIV ribozymes delivered by the vector will be evaluated in transduced CD34+ cells derived from AIDS lymphoma patients in preclinical studies. Finally, a clinical trial of HIV-vector transduced ASCT will be completed in a study of AIDS- related non-Hodgkin's lymphoma and Hodgkin's disease. Methods for the production of helper free HIV vectors will utilize ribozymes that target HIV sequences that are not included in the vector and sequences of VSV-G that are crucial to vector packaging. The candidate HIV-vector chosen for clinical trial will have been exhaustively analyzed for absence of helper virus. In addition to protection of the production lot from contamination with helper virus, this vector will also encode anti-HIV ribozymes that could potentially have activities in vivo against HIV-1 infection and influence long-term survival This project will advance the theme of the Program by seeking to improve the outcome of transplantation for hematologic malignancy. In addition, interactions of Project II, Project IV, and Project V, in which HIV-vectors and AAV- vectors are evaluated for stem cell gene delivery, will permit a comparison of these vectors within a similar patients groups for transduction efficiency, cell engraftment, and duration of transgene expression.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Cancer Institute (NCI)
• Type: Research Program Projects (P01)
• Project #: 5P01CA030206-21
• Application #: 6588105
• Study Section: Subcommittee E - Prevention &Control (NCI)
• Project Start: 2002-04-24
• Project End: 2003-03-31
• Support Year: 21
• Fiscal Year: 2002

Institution

• Name: City of Hope National Medical Center
• City: Duarte
• State: CA
• Country: United States
• Zip Code: 91010

Publications

Limaye, Ajit P; La Rosa, Corinna; Longmate, Jeff et al. (2016) Plasma IL-10 Levels to Guide Antiviral Prophylaxis Prevention of Late-Onset Cytomegalovirus Disease, in High Risk Solid Kidney and Liver Transplant Recipients. Transplantation 100:210-6

Jonnalagadda, Mahesh; Mardiros, Armen; Urak, Ryan et al. (2015) Chimeric antigen receptors with mutated IgG4 Fc spacer avoid fc receptor binding and improve T cell persistence and antitumor efficacy. Mol Ther 23:757-68

Wang, Xiuli; Wong, ChingLam W; Urak, Ryan et al. (2015) CMVpp65 Vaccine Enhances the Antitumor Efficacy of Adoptively Transferred CD19-Redirected CMV-Specific T Cells. Clin Cancer Res 21:2993-3002

Mardiros, Armen; Forman, Stephen J; Budde, Lihua E (2015) T cells expressing CD123 chimeric antigen receptors for treatment of acute myeloid leukemia. Curr Opin Hematol 22:484-8

Caruso, Hillary G; Hurton, Lenka V; Najjar, Amer et al. (2015) Tuning Sensitivity of CAR to EGFR Density Limits Recognition of Normal Tissue While Maintaining Potent Antitumor Activity. Cancer Res 75:3505-18

Israyelyan, A; Goldstein, L; Tsai, W et al. (2015) Real-time assessment of relapse risk based on the WT1 marker in acute leukemia and myelodysplastic syndrome patients after hematopoietic cell transplantation. Bone Marrow Transplant 50:26-33

Wussow, Felix; Chiuppesi, Flavia; Martinez, Joy et al. (2014) Human cytomegalovirus vaccine based on the envelope gH/gL pentamer complex. PLoS Pathog 10:e1004524

Rushworth, David; Jena, Bipulendu; Olivares, Simon et al. (2014) Universal artificial antigen presenting cells to selectively propagate T cells expressing chimeric antigen receptor independent of specificity. J Immunother 37:204-13

Jena, Bipulendu; Moyes, Judy S; Huls, Helen et al. (2014) Driving CAR-based T-cell therapy to success. Curr Hematol Malig Rep 9:50-6

Singh, Harjeet; Huls, Helen; Kebriaei, Partow et al. (2014) A new approach to gene therapy using Sleeping Beauty to genetically modify clinical-grade T cells to target CD19. Immunol Rev 257:181-90