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Lentiviral-MGMT gene transfer into hematopoietic stem cells

Award Number: R42CA128269
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2010
PERIOD OF PERFORMANCE END DATE: 08/31/2015

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Lentiviral-MGMT gene transfer into hematopoietic stem cells - DESCRIPTION (provided by applicant): Therapeutic stem cell gene transfer relies on long-term gene expression achieved by integration of new DNA into the cellular genome. Current clinical trials featuring oncoretroviruses have encountered a number of roadblocks that include low levels of gene transfer, poor expression, and a recognized preferential insertion near promoter regions that increases the chance for insertional mutagenesis and leukemia. This proposal will link the advances made at Lentigen Corp. in large scale production of the newest generation lentiviral vectors (LV) with the clinical need for transferring the MGMT gene into hematopoietic stem cells. The goal of this application is to optimize the safety of lentiviral gene transfer of MGMT using preclinical assays followed by a clinical trial using this vector in cancer patients. Expression of the MGMT (O6-methylguanine-DNA- methyltransferase) enzyme has been established as an effective method for hematopoietic progenitor (HP) selection in vivo. The MGMT gene product (also known as AGT, O6-alkylguanine-DNA-alkyltransferase) repairs DNA damaged by alkylating agents. Hematopoietic progenitor cells (HP) can be transduced with a vector containing MGMT and selected for in vivo by administration of a DNA damaging drug therapy, i.e. the alkylating agent Temozolomide, whose potency is increase by co-administration of O6-benzylguanine (BG), a therapeutic inhibitor of the naturally occurring AGT. Using a well-characterized singe point mutation of MGMT, P140K, that is resistant to the inhibitory effects of BG, it is possible to selectively protect HP from the drug combination, providing a unique enrichment strategy for multilineage progenitors in vivo. LVs, a subclass of retroviral vectors, offer several advantages over oncoretroviral vectors including increased transduction efficiencies, long-term gene expression without silencing, and decreased risk of insertional oncogenesis. In Phase I of this application we will generate cGMP vector with improved safety characteristics, analyze the insertion site frequency and preference, and create a publically available database to share this information with other investigators and regulatory agencies. This will set a new standard in the field for sharing data generated from the use of a clinical gene vector with human cells. In the Phase II portion of this application, a clinical trial designed to demonstrate safe use of lentiviral vector with the potential to improve outcomes for patients with advanced glioma, will be initiated. This trial will be the first in man study of in vivo stem cell selection mediated by a drug resistance gene. This trial is of importance not only for patients with glioma, but as means to demonstrate the effective development of a platform for selecting gene-modified stem cells that could also be used for the correction of numerous monogenic disorders. PUBLIC HEALTH RELEVANCE: This proposal is a combined phase I and phase II application, Fast-Track, that will evaluate lentiviral gene vectors expressing the MGMT gene in pre-clinical models and in a clinical trial for glioma. The goal of this application is to optimize the safety of lentiviral gene transfer of MGMT. Demonstration of the safe use of this lentiviral vector in clinical studies will open the door to the treatment of not only glioma, but other malignancies in which hematotoxicity is a major side-effect, or in which malignant stem cells are replaced by donor-derived (allogeneic) or patient-derived (autologous) stem cells that can be selected for in vivo. Thus, this proposal represents a first step in improving the efficacy of stem cell therapeutics by providing the means to increase the number of cells carrying the gene to greater and potentially therapeutic levels.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2015 ( Subtotal = $0 )
2015	2011	LENTIGEN CORPORATION	910 CLOPPER ROAD SUITE 200S	GAITHERSBURG	MD	20878	MONTGOMERY	USA	Cancer Treatment Research	000	2	10/24/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $0 )
2014	2011	LENTIGEN CORPORATION	910 CLOPPER ROAD SUITE 200S	GAITHERSBURG	MD	20878	MONTGOMERY	USA	Cancer Treatment Research	000	2	3/7/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2011 ( Subtotal = $2,150,576 )
2011	2011	LENTIGEN CORPORATION	1450 SOUTH ROLLING ROAD	BALTIMORE	MD	21227	BALTIMORE	USA	Cancer Treatment Research	000	2	8/31/2011	NON-COMPETING CONTINUATION	$2,150,576
														Subtotal = $2,150,576

Issue Date FY: 2010 ( Subtotal = $502,085 )
2010	2010	LENTIGEN CORPORATION	1450 SOUTH ROLLING ROAD	BALTIMORE	MD	21227	BALTIMORE	USA	Cancer Treatment Research	000	1	9/30/2010	NEW	$502,085
														Subtotal = $502,085

Grand Total All Awards = $2,652,661

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Lentiviral-MGMT gene transfer into hematopoietic stem cells

Award Number: R42CA128269

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2010

PERIOD OF PERFORMANCE END DATE: 08/31/2015

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