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Immunomodulation of the Tumor Microenvironment with Molecular Targeted Radiotherapy to Facilitate an Adaptive Anti-Tumor Immune Response to Combined Modality Immunotherapies

Award Number: U01CA233102
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT We are developing a combined modality therapeutic approach to eradicating metastatic cancers that are immunologically “cold” and do not respond to immune checkpoint inhibition (ICI). Using an “in situ vaccine” regimen consisting of 12 Gy focal external beam radiation therapy (EBRT) and intratumoral (IT) injection of tumor-specific antibody (mAb) + IL2, we have eradicated solitary, large, cold syngeneic tumors in mice. This in situ vaccine converts the targeted tumor into a focus of enhanced tumor antigen presentation resulting in increased T-cell infiltration and potent T-cell memory. However, the presence of an identical but untreated second tumor (2°) on a mouse’s opposite flank inhibits the effect of this treatment, preventing eradication of the primary (1°) tumor treated with EBRT + IT mAb-IL2. In this setting, the untreated 2° tumor causes tumor- specific immune unresponsiveness to EBRT + IT mAb-IL2 at the 1° tumor. We refer to this as concomitant immune tolerance (CIT). We can overcome CIT, and eliminate both tumors by giving IT mAb-IL2 to the 1° tumor and EBRT to both the 1° and 2° tumors. Delivering as little as 2 Gy EBRT to the 2° tumor can overcome CIT. Clinically, delivery of EBRT (even low dose) to all sites of metastatic disease is problematic, but this can effectively be achieved using molecular targeted radiation therapy (MTRT). MTRT is increasingly entering clinical oncology practice and our UW team has led preclinical and clinical testing of a novel class of MTRT using alkylphosphocholine (APCh) analogs that selectively deliver radiation to cancers in vivo. These show tumor-selective uptake in virtually all mammalian tumor cells and tumor locations tested (including > 90 tumor lines and in patients across various clinical trials). In a syngeneic murine melanoma model, we have observed a potent synergy between systemically administered ICI and MTRT delivered using our next-generation APC analog, 90Y-NM600. In a project that builds upon the ongoing collaborative progress of our multidisciplinary team, we will now systematically optimize the potency of combining MTRT 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 MTRT and ICI, 2) evaluate the capacity of MTRT to overcome CIT and enhance systemic anti-tumor immune response in the setting of multiple tumors where one is treated with in situ vaccine (EBRT + IT mAb-IL2) alone or in combination with ICI. Because murine models do not replicate the size and spatial distribution of human metastatic cancer and because these factors strongly influence the dosimetry of MTRT, we will test the immunomodulatory effects of MTRT + in situ vaccine in large breed companion canines (pet dogs) with naturally occurring metastatic melanoma. 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: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	5	3/20/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $930,219 )
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	4	12/14/2021	SUPPLEMENT FOR EXPANSION	$165,219
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	5	8/3/2022	NON-COMPETING CONTINUATION	$765,000
														Subtotal = $930,219

Issue Date FY: 2021 ( Subtotal = $765,000 )
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	4	8/26/2021	NON-COMPETING CONTINUATION	$765,000
														Subtotal = $765,000

Issue Date FY: 2020 ( Subtotal = $765,000 )
2020	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	3	8/31/2020	NON-COMPETING CONTINUATION	$765,000
														Subtotal = $765,000

Issue Date FY: 2019 ( Subtotal = $765,000 )
2019	2019	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	2	9/3/2019	NON-COMPETING CONTINUATION	$765,000
														Subtotal = $765,000

Issue Date FY: 2018 ( Subtotal = $765,000 )
2018	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	9/18/2018	NEW	$765,000
														Subtotal = $765,000

Grand Total All Awards = $3,990,219

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Immunomodulation of the Tumor Microenvironment with Molecular Targeted Radiotherapy to Facilitate an Adaptive Anti-Tumor Immune Response to Combined Modality Immunotherapies

Award Number: U01CA233102

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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