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Repolarizing the Tumor and Metastatic Microenvironments to Treat Patients with Pancreatic Cancer

Award Number: R01CA262580
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/02/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Repolarizing the Tumor and Metastatic Microenvironments to Treat Patients with Pancreatic Cancer - Pancreatic ductal adenocarcinoma cancer (PDAC) is the 3rd most common cause of cancer deaths in the United States with a dismal 5-year overall survival of 9%. Surgical intervention is currently the only cure for PDAC, however, 80% of patients are deemed unresectable at presentation due to locally advanced and/or metastatic disease. Existing therapies are often unable to downsize locally advanced PDAC (LAPC) for surgical candidacy, and are also ineffective at providing distal tumor control. Therapeutic approaches capable of both local downstaging and recurrent/metastatic tumor control are desperately needed to improve resectability rates. This application will address the unmet need by translating an innovative combination immunotherapy to the clinic and exploring its effects on LAPC in humans. Our recently published work demonstrated that stereotactic body radiotherapy (SBRT), a less toxic, more effective strategy that focuses higher dose radiation precisely to the tumor, combined with the potent immune cell–stimulating cytokine interleukin-12 (IL-12) encapsulated in polymer microspheres (IL-12MS) resulted in remarkable tumor control and durable cure in preclinical models. Microsphere technology represents an innovative tool that provides a slow, continuous release of cytokine intratumorally while also protecting the labile IL-12 protein from degradation by proteases. The combination of SBRT with IL-12MS not only strongly stimulated the adaptive arm of the immune system including cytotoxic T cells to destroy pancreatic tumor cells, but also had a repolarizing effect on cells of innate immune system converting typically immunosuppressive myeloid cells into ones with immunostimulatory potential. Moving this promising therapy into the clinic, we hypothesize that combined SBRT/IL-12MS therapy is safe and tolerable, and will improve progression-free survival and tumor downstaging to enable resection in LAPC. In Aim 1, we will establish a clinical trial exploring the first-in-human use of SBRT followed by ultrasound- guided IL-12MS delivery in patients with unresectable LAPC. The main objective is to evaluate safety and tolerability, and the secondary objective is to evaluate efficacy and overall outcome. Aim 2 will perform corollary studies on peripheral blood along with baseline and on-study tumor biopsies collected from enrolled patients. These data will address whether SBRT/IL-12MS repolarizes the tumor microenvironment (TME) from an immunologically “cold” tumor to one that is immunologically “hot”. Aim 3 will utilize preclinical modelling to develop a strategy to treat metastatic PDAC using SBRT/IL-12MS therapy. These results are essential in order to expand this therapy into metastatic patients where there are little to no effective treatments. Overall, our proposed application builds on promising preclinical data showing the potential efficacy of combined SBRT/IL- 12MS therapy for patients with LAPC/metastatic lesions. This technologically innovative strategy utilizes a unique strategy of repolarizing the TME to treat this recalcitrant malignancy for which there are few effective therapies.


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 = $490,237 )
2024	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Cancer Treatment Research	000	3	4/24/2024	NON-COMPETING CONTINUATION	$490,237
														Subtotal = $490,237

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Cancer Treatment Research	000	2	9/18/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $516,038 )
2022	2022	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Cancer Treatment Research	000	2	8/12/2022	NON-COMPETING CONTINUATION	$516,038
														Subtotal = $516,038

Issue Date FY: 2021 ( Subtotal = $516,038 )
2021	2021	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Cancer Treatment Research	000	1	8/2/2021	NEW	$516,038
														Subtotal = $516,038

Grand Total All Awards = $1,522,313

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Repolarizing the Tumor and Metastatic Microenvironments to Treat Patients with Pancreatic Cancer

Award Number: R01CA262580

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/02/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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