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Systemic delivery of an oncolytic adenovirus targeting TGFβ to enhance anti-PD-1 and anti-CTLA-4 therapy for triple negative breast cancer

Award Number: R01CA248574
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Systemic delivery of an oncolytic adenovirus targeting TGFβ to enhance anti-PD-1 and anti-CTLA-4 therapy for triple negative breast cancer - PROJECT SUMMARY The development of novel therapies for the treatment of breast cancer is a major unmet need. In recent years, immune checkpoint inhibitors including anti-PD-1, anti-PD-L1 and anti-CTLA-4 have shown promise as antitumor agents, and are approved for the treatment of several malignancies. Clinical trials in breast cancer patients have shown that about 20% of triple negative breast cancers (TNBC) respond favorably to anti-PD-1 antibodies and Atezolizumab, an anti-PD-L1 antibody in combination with nab-paclitaxel (Abraxane) is now FDA approved for advanced stage TNBC patients with positive PDL-1 expression. However, many TNBC patients are resistant to anti-PD-1/PDL-1 and anti-CTLA-4 treatments which could be due to weak immunogenicity of the tumors and poor inflammatory but highly immune suppressive tumor microenvironment. In recent years TGFβ has been shown to be a strong immune suppressor and can potentially produce a tumor microenvironment that is resistant to anti-PD-1 and anti-CTLA-4 therapy. To overcome resistance to anti-PD-1 and anti-CTLA-4 we have developed adenoviruses (Ad) expressing sTGFβRIIFc (soluble TGFβ receptor II fused with human IgG Fc). sTGFβRIIFc acts as a TGFβ decoy, and can inhibit TGFβ pathways. Initially, we created Ad5 based Ad.sT expressing sTGFβRIIFc. To reduce hepatic/systemic toxicity associated with systemic delivery of Ad.sT, we created mHAd.sT, a liver-detargeted virus, by replacing hypervariable regions (HVRs) (1-7) of Ad.sT with Ad48 HVRs. To enhance tumor specificity, we have now created mHAdLyp.sT by introducing LyP-1 peptide, a 9-amino acid long tumor homing-cell peptide, into the HI loop of the mHAd.sT fiber. In this proposal, we will test the hypotheses that systemic administration of mHAdLyp.sT in mice bearing 4T1 triple negative mammary tumors will result in reduced hepatic/systemic toxicity but produce high levels of sTGFβRIIFc and inhibit TGFβ pathways. This will alter the tumor microenvironment, induce tumor immunity, and overcome resistance to anti-PD-1 and anti-CTLA-4., and examine the expression profiles of TGFβ-1, TGFβ-1 regulated genes, and PD-1 and CTLA-4 signaling pathways. We will examine immuno-phenotypes in tumors, peripheral blood and spleen (Aim 1). Next, we will examine mHAdLyp.sT, anti-PD-1 and anti-CTLA-4 combination therapies in mouse tumor models. We will conduct RNA-Seq analysis of the whole transcriptomes, and examine the role of immune activation in mediating the anti-tumor responses (Aim 2). We will test the hypothesis that systemic administration of mHLypAd.sT, in combination with anti-PD-1 and anti- CTLA-4 in mice with pre-established metastases will be effective (Aim 3). To guide us for the combination therapy trials with mHAdLyp.sT, anti-PD-1 and anti-CTLA-4, we will examine human TNBC tumors by Nanostring technology for RNA profiling, and will further examine the TGFβ-1 and other relevant biomarkers and TILS in human TNBC tumors. We will also screen the human population for the Ad neutralizing antibodies titers (Aim 4). We believe that our research described here is critical to bring forward our oncolytic virus mHAdLyp.sT targeting TGFβ in combination with anti-PD-1 and anti-CTLA-4 for clinical evaluation in TNBC patients.


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: 2025 ( Subtotal = $374,662 )
2025	2025	ENDEAVOR HEALTH CLINICAL OPERATIONS	1301 CENTRAL ST	EVANSTON	IL	60201	COOK	USA	Cancer Treatment Research	000	5	1/24/2025	NON-COMPETING CONTINUATION	$374,662
														Subtotal = $374,662

Issue Date FY: 2024 ( Subtotal = $396,958 )
2024	2024	NORTHSHORE UNIVERSITY HEALTHSYSTEM	SUITE 301	EVANSTON	IL	60201	COOK	USA	Cancer Treatment Research	000	4	3/15/2024	NON-COMPETING CONTINUATION	$376,065
2024	2024	NORTHSHORE UNIVERSITY HEALTHSYSTEM	SUITE 301	EVANSTON	IL	60201	COOK	USA	Cancer Treatment Research	001	4	7/10/2024	NON-COMPETING CONTINUATION	$20,893
														Subtotal = $396,958

Issue Date FY: 2023 ( Subtotal = $378,315 )
2023	2023	NORTHSHORE UNIVERSITY HEALTHSYSTEM	SUITE 301	EVANSTON	IL	60201	COOK	USA	Cancer Treatment Research	000	3	2/17/2023	NON-COMPETING CONTINUATION	$378,315
														Subtotal = $378,315

Issue Date FY: 2022 ( Subtotal = $374,436 )
2022	2022	NORTHSHORE UNIVERSITY HEALTHSYSTEM	1301 CENTRAL ST	EVANSTON	IL	60201	COOK	USA	Cancer Treatment Research	002	2	5/19/2022	NON-COMPETING CONTINUATION	$30,569
2022	2022	NORTHSHORE UNIVERSITY HEALTHSYSTEM	1301 CENTRAL ST	EVANSTON	IL	60201	COOK	USA	Cancer Treatment Research	001	2	2/7/2022	NON-COMPETING CONTINUATION	$343,867
2022	2021	NORTHSHORE UNIVERSITY HEALTHSYSTEM	1301 CENTRAL ST	EVANSTON	IL	60201	COOK	USA	Cancer Treatment Research	000	1	10/15/2021	NEW	$0
														Subtotal = $374,436

Issue Date FY: 2021 ( Subtotal = $395,126 )
2021	2021	NORTHSHORE UNIVERSITY HEALTHSYSTEM	1301 CENTRAL ST	EVANSTON	IL	60201	COOK	USA	Cancer Treatment Research	000	1	2/22/2021	NEW	$395,126
														Subtotal = $395,126

Grand Total All Awards = $1,919,497

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Systemic delivery of an oncolytic adenovirus targeting TGFβ to enhance anti-PD-1 and anti-CTLA-4 therapy for triple negative breast cancer

Award Number: R01CA248574

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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