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Tumor Stroma Breaking System for Efficient Delivery of Therapeutic Agents

Award Number: R41CA247165
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/23/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Tumor Stroma Breaking System for Efficient Delivery of Therapeutic Agents - Cancer immunotherapy using adoptive T cell transfer has shown its promises in the treatment of hematological malignancies. Despite tremendous efforts, results of clinical trials using tumor infiltrating lymphocytes or engineered CAR-T cells in human solid tumors have not produced desired therapeutic responses. In solid tumors, there are multiple barriers that prevent cytotoxic T cells reaching tumor cells. First, abnormal blood vessels limit T cell delivery into solid tumors, especially tumor center. The presence of dense tumor stromal cells and extracellular matrix create a physical barrier that traps T cells in an immunosuppressive stroma microenvironment. Therefore, there is an unmet need to develop novel approaches to improve delivery efficiency of cytotoxic T cells in solid tumors. The translational goal of the proposed phase I research is to develop and validate a stroma-breaking therapeutic T cell delivery system for immunotherapy in human solid tumors with a focus on pancreatic and colon cancers. We have developed a receptor targeted and stroma breaking drug delivery platform with novel designs to overcome tumor stromal cellular and extracellular matrix barriers. We have demonstrated its ability to deliver nanoparticle-drug crossing tumor vessels, migrating through tumor stroma, and penetrating the basement membrane to reach tumor cells. This recombinant targeting ligand consists of urokinase plasminogen activator receptor (uPAR) binding domain of uPA fused with the catalytic domain of matrix metalloproteinase-14 (ATFmmp14). Our preliminary results showed that co-delivery of T cells with ATFmmp14 ligands led to significant increases in the numbers of T cells delivered in tumors following intravenous delivery in mouse colon and pancreatic tumor models as well as a human colon cancer patient derived xenograft (PDX) model. In this phase I project, we aim to determine the effect of ATFmmp14-T cell delivery system on intratumoral delivery and distribution using the MHC-non-restricted cytotoxic ɣδ T cells as a T cell model system in human colon and pancreatic cancer PDX models. First, we will develop the best formulation of ATFmmp14 conjugated T cell delivery platform using ɣδ T cells obtained from healthy donors in human pancreatic and colon PDX models (Aim1). Next, we will determine whether ATFmmp14 ligand can improve selective delivery of ɣδ T cells into pancreatic and colon PDX tumors and promote cell migration through stroma and basement membrane barriers to reach tumor cells (Aim 2). Biodistribution and systemic toxicity in normal organs and tissues will also be evaluated (Aim 2). Finally, the therapeutic efficacy of targeted delivery of ɣδ T cells without or with the combination of a chemotherapy drug will be determined in pancreatic and colon PDX models (Aim 3). Results of the above proposed studies should allow us building a strong foundation for conducting further translational studies in the Phase II research project to bring this approach into a clinical trial. Result of this study will also lead to future development and commercialization of this unique approach for other adaptive T transfer therapies, such as CAR-T, tumor specific T cells, and tumor infiltrating T cells.


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: 2024 ( Subtotal = $0 )
2024	2020	MIGRA-THERAPEUTICS, LLC	1750 HAYGOOD DR NE	ATLANTA	GA	30322	DEKALB	USA	Cancer Treatment Research	000	1	2/1/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	MIGRA-THERAPEUTICS, LLC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	1	6/3/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2020	MIGRA-THERAPEUTICS, LLC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Cancer Treatment Research	000	1	6/3/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $330,363 )
2020	2020	MIGRA-THERAPEUTICS, LLC	3175 PRESIDENTIAL DR SUITE B	ATLANTA	GA	30340	DEKALB	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	1	9/17/2020	SUPPLEMENT FOR EXPANSION	$105,503
2020	2020	MIGRA-THERAPEUTICS, LLC	3175 PRESIDENTIAL DR SUITE B	ATLANTA	GA	30340	DEKALB	USA	Cancer Treatment Research	000	1	6/23/2020	NEW	$224,860
														Subtotal = $330,363

Grand Total All Awards = $330,363

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Tumor Stroma Breaking System for Efficient Delivery of Therapeutic Agents

Award Number: R41CA247165

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/23/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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