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Anti-Complement Immunotherapy for Pancreatic Cancer

Award Number: F30CA278322
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Anti-Complement Immunotherapy for Pancreatic Cancer - PROJECT SUMMARY / ABSTRACT Pancreatic Ductal Adenocarcinoma (PDAC) is an almost uniformly lethal disease, with an overall survival under 10%. Despite therapeutic advances in all arenas of cancer treatment, including immunotherapy, overall survival has not significantly improved in PDAC, representing a critical need for the development of novel therapeutic strategies for this disease. The tumor microenvironment (TME) in PDAC is characterized by an immunosuppressive infiltrate causing T-cell exclusion, and dense stromal desmoplasia. The complement cascade is activated in the PDAC TME and may promote this uniquely challenging TME by signaling to immune cells and fibroblasts expressing complement receptors. Complement activation has previously been demonstrated to promote infiltration of immune cells which contribute to T-cell exclusion in multiple tumor types in a context-dependent fashion. The long-term objectives of this project are to understand microenvironmental mechanisms by which complement promotes oncogenesis in PDAC, and to elucidate the interactions between radiotherapy (RT) and complement blockade in PDAC. A novel autochthonous mouse model of PDAC was generated and crossed with complement deficient C3 knockout (KO) mice to allow for studies which define the role of complement in PDAC. Tumor growth in complement-proficient wild type (WT) PDAC mice and C3 KO PDAC mice will be tracked using serial, PET/CT imaging. Tumors will be assessed histologically from 3-6 months after induction with tamoxifen to determine histologic grade, normal acinar area, and fibrotic area. Flow cytometry will be used to determine the impact of complement on infiltrating immune cells while single-cell RNA-sequencing will provide insight into the development and activation of cancer-associated fibroblasts. We will also assess the role of tumor cell vs. stromally derived C3 with shRNA depletion of C3 in YFP-expressing KPC cells (KPCY) in flank tumor growth studies in WT and C3 KO mice as a second model to confirm these results. To assess the impact of photon, proton, and carbon ion RT on complement activation and immune tolerance we will irradiate KPCY using each radiation modality. Complement deposition assays will be performed by culturing irradiated and non-treated tumor cells in the presence of serum as a complement source, before measuring activation by flow cytometry. Next, dendritic cells will be co-cultured with irradiated and non-irradiated KPCY cells with serum to determine if complement deposition on irradiated tumor cells reduces dendritic cell activation markers measured by flow cytometry. Translational studies will be performed using neutralizing antibodies and small molecule inhibitors to blockade complement signaling alone and with RT in an orthotopic KPCY model. Mice will be treated with neutralizing antibodies and inhibitors to blockade complement signaling and irradiated with an X- strahl Small Animal Radiation Research Platform or a Varian ProBeam proton therapy machine and growth will be tracked by IVIS. Complement activation will be assessed by western blot and immunofluorescence, and flow cytometry will assess differences in infiltrating immune cells post-irradiation.


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: 2026 ( Subtotal = $54,538 )
2026	2026	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Research Manpower	000	3	1/7/2026	NON-COMPETING CONTINUATION	$54,538
														Subtotal = $54,538

Issue Date FY: 2025 ( Subtotal = $54,538 )
2025	2025	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Research Manpower	000	2	1/13/2025	NON-COMPETING CONTINUATION	$53,974
2025	2025	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Research Manpower	001	2	6/13/2025	NON-COMPETING CONTINUATION	$564
														Subtotal = $54,538

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Research Manpower	000	1	6/30/2023	NEW	$52,694
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Research Manpower	001	1	6/30/2023	NEW	$0
														Subtotal = $52,694

Grand Total All Awards = $161,770

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Anti-Complement Immunotherapy for Pancreatic Cancer

Award Number: F30CA278322

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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