Hematopoietic stem cell (HSC) gene therapy has been shown to result in substantial improvement and even cure for a number of diseases such as hemoglobinopathies and adrenoleukodystrophy. In addition, HSC transplantation has recently been shown to result in the cure of HIV when HIV-resistant donor cells from a donor with a rare mutation in the HIV co-receptor CCR5 were used in an allogeneic transplantation. While this study showed that transplantation of CCR5-negative cells could result in an HIV cure, finding an HLA-matched CCR5-negative donor is exceedingly rare. Thus as a surrogate approach many investigators are exploring the use of genetically modified HIV-resistant autologous cells. However, relatively high levels of genetically modified/HIV resistant cells are necessary and this can often not be achieved even after a myeloablative conditioning regimen. We have shown in a nonhuman primate model using HSCs gene-modified with a MGMTP140K mutant transgene that we can achieve efficient increases of gene-modified cells in vivo. Thus, we would like to test this strategy in a patient population that has been shown to benefit from an autologous transplantation and that may also benefit from both the anti-tumor effect of low-dose chemotherapy used for in vivo selection and from the resulting increased levels of genetically modified and HIV-resistant HSCs. We have previously shown that we can achieve low-level engraftment of gene-modified HIV-resistant cells in patients with AIDS-related lymphoma. However, engraftment of gene-modified cells was too low to result in any significant therapeutic benefit. In the current application, we propose to use a potent HIV entry inhibitor (C46) and the potent P140K selection cassette to increase the level of gene-modified HIV resistant cells in patients. The use of in vivo selection would have wide applications not only for the treatment of HIV but also genetic diseases and in particular hemoglobinopathies where high levels of gene-modified cells are necessary to alleviate all clinical manifestations of the disease. A major strength of this proposal is the collaboration between investigators from two institutions with unique expertise in the fields of gene therapy, transplantation and clinical HIV. Our overall hypothesis is that an autologous HSC transplantation with cells gene-modified with a potent anti-HIV transgene will lead to control of HIV and associated complications. Furthermore, inclusion of a potent in vivo selection transgene, P140K, will allow us to significantly increase the levels of HIV-resistant CD4 cells following transplantation. Based on extensive preclinical data from our nonhuman primate studies, we hypothesize that the levels of gene-modified, HIV-resistant HSCs and HSC-derived T cells obtained with our proposed approach will allow for an improved immune response and control or elimination of HIV and thus cure.

Public Health Relevance

We propose the use of stem cell transplantation and a novel gene therapy approach to treat patients with AIDS lymphoma and hopefully cure not only the lymphoma but also HIV. This approach would have wide applications for the treatment of patients with HIV and genetic blood diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL116217-05
Application #
9273593
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Zou, Shimian
Project Start
2012-08-01
Project End
2018-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
5
Fiscal Year
2017
Total Cost
$523,418
Indirect Cost
$188,478
Name
Fred Hutchinson Cancer Research Center
Department
Type
Research Institutes
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Colonna, Lucrezia; Peterson, Christopher W; Schell, John B et al. (2018) Evidence for persistence of the SHIV reservoir early after MHC haploidentical hematopoietic stem cell transplantation. Nat Commun 9:4438
Paul, Biswajit; Ibarra, Guillermo S Romano; Hubbard, Nicholas et al. (2018) Efficient Enrichment of Gene-Modified Primary T Cells via CCR5-Targeted Integration of Mutant Dihydrofolate Reductase. Mol Ther Methods Clin Dev 9:347-357
Adair, Jennifer E; Kubek, Sara P; Kiem, Hans-Peter (2017) Hematopoietic Stem Cell Approaches to Cancer. Hematol Oncol Clin North Am 31:897-912
Reeves, Daniel B; Peterson, Christopher W; Kiem, Hans-Peter et al. (2017) Autologous Stem Cell Transplantation Disrupts Adaptive Immune Responses during Rebound Simian/Human Immunodeficiency Virus Viremia. J Virol 91:
Peterson, Christopher W; Benne, Clarisse; Polacino, Patricia et al. (2017) Loss of immune homeostasis dictates SHIV rebound after stem-cell transplantation. JCI Insight 2:e91230
Peterson, Christopher W; Wang, Jianbin; Norman, Krystin K et al. (2016) Long-term multilineage engraftment of autologous genome-edited hematopoietic stem cells in nonhuman primates. Blood 127:2416-26
Romano Ibarra, Guillermo S; Paul, Biswajit; Sather, Blythe D et al. (2016) Efficient Modification of the CCR5 Locus in Primary Human T Cells With megaTAL Nuclease Establishes HIV-1 Resistance. Mol Ther Nucleic Acids 5:e352
Adair, Jennifer E; Waters, Timothy; Haworth, Kevin G et al. (2016) Semi-automated closed system manufacturing of lentivirus gene-modified haematopoietic stem cells for gene therapy. Nat Commun 7:13173
Dimitrov, Dobromir T; Kiem, Hans-Peter; Jerome, Keith R et al. (2016) A curative regimen would decrease HIV prevalence but not HIV incidence unless targeted to an ART-naïve population. Sci Rep 6:22183
Humbert, Olivier; Gisch, Don W; Wohlfahrt, Martin E et al. (2016) Development of Third-generation Cocal Envelope Producer Cell Lines for Robust Lentiviral Gene Transfer into Hematopoietic Stem Cells and T-cells. Mol Ther 24:1237-46

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