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Targeted radionuclide therapy for tumor immunomodulation and enhancing immunotherapy response

Award Number: F30CA268780
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Targeted radionuclide therapy for tumor immunomodulation and enhancing immunotherapy response - Project Summary/Abstract We aim to improve the cure rates for metastatic cancers. To achieve this we propose a combined modality approach to stimulate and diversify an endogenous anti-tumor immune response at all tumor sites to recognize and destroy tumor cells in a manner that will prevent recurrence and enable long-term cancer free survival. Immune checkpoint inhibitors (ICI; e.g. anti-PD-L1), are a class of immunotherapies that modulate immune tolerance of a tumor by blocking specific inhibitory receptor-ligand interactions on the surface of T cells and thereby overcoming T cell inhibition or exhaustion. In patients with immunologically “hot” tumors, characterized by a pre-existing but exhausted anti-tumor immune response, ICIs can restore efficacy to the anti-tumor immune response, sometimes resulting in complete and durable tumor regression. However, ICIs have not shown clinical benefit in the treatment of immunologically “cold” cancers that are characterized by low levels of T cell infiltrate and low mutation burden resulting in few mutation-created neo-antigens. To overcome immunotherapy treatment barriers posed by immunologically cold tumors, we propose to combine systemic delivery of ICIs with systemic delivery of radiation by targeted radionuclide therapy (TRT). To date, nearly all approaches to combining radiation and immunotherapy have used external beam radiotherapy (EBRT), which promotes tumor immune cell infiltration through activation of type I interferon (IFN) responses. Administration of EBRT to multiple tumor sites or to the whole body (to target radiographically occult or microscopic disease) would result in prohibitive toxicity, including lymphopenia. TRT is a systemic method of delivering a therapeutic radionuclide to a tumor, which poses an alternative option for delivery of immunomodulatory radiation to metastatic tumor sites without causing immunosuppression. The Weichert lab at the University of Wisconsin-Madison has developed a novel class of TRT, known as NM600, an alkylphosphocholine analog that is selectively taken up and retained in nearly any tumor type in any location. Our broad hypothesis is that unique physical properties of radionuclides (e.g. emission type, linear energy transfer, half-life, tissue range) differentially impact immunomodulation by TRT. In this study, the immunomodulatory capacity of alpha- (225Ac) and beta- (90Y) particle emitting radionuclides will be compared directly. In a project that builds upon the ongoing collaborative progress of the Morris and Weichert labs, we will now determine the radionuclide-specific potency of combining TRT with immunotherapy to enhance the immune response against immunologically cold tumors. In murine models, we will: 1) expand on preliminary data showing potent synergy with the combination of TRT and ICI, 2) evaluate therapeutic mechanisms of TRT and ICI using the intrinsic properties of 225Ac- and 90Y-NM600, focusing on type I IFN response activation and 3) investigate potential enhanced tumor responses with the combination of two distinct radionuclides with ICI. The insights and treatment regimens developed in these studies should enable rapid translation to clinical testing in patients and potentially for any type of metastatic cancer.


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 = $43,552 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Research Manpower	000	4	1/10/2025	NON-COMPETING CONTINUATION	$43,552
														Subtotal = $43,552

Issue Date FY: 2024 ( Subtotal = $45,705 )
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Research Manpower	000	3	12/1/2023	NON-COMPETING CONTINUATION	$44,425
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Research Manpower	001	3	5/7/2024	NON-COMPETING CONTINUATION	$1,280
														Subtotal = $45,705

Issue Date FY: 2023 ( Subtotal = $38,138 )
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Research Manpower	001	2	6/6/2023	NON-COMPETING CONTINUATION	$942
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Research Manpower	000	2	12/27/2022	NON-COMPETING CONTINUATION	$37,196
														Subtotal = $38,138

Issue Date FY: 2022 ( Subtotal = $37,196 )
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Research Manpower	002	1	8/12/2022	NEW	$716
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Cancer Research Manpower	000	1	12/3/2021	NEW	$36,480
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Research Manpower	001	1	12/3/2021	NEW	$0
														Subtotal = $37,196

Grand Total All Awards = $164,591

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Targeted radionuclide therapy for tumor immunomodulation and enhancing immunotherapy response

Award Number: F30CA268780

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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