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Targeting dual functions of PD-L1 for cancer therapy

Award Number: R01CA256927
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Targeting dual functions of PD-L1 for cancer therapy - Abstract Targeting immune checkpoint signaling with blocking antibodies has reached a limitation in the treatment of advanced cancers. Although antibodies that bind programmed death ligand 1 (PD-L1) are effective in blocking PD-L1's extracellular interaction with PD-1 receptor on T cells, the potential adaptive upregulation of PD-L1 and its recycling from intracellular compartment to the cell surface may compromise their efficacy. Importantly, the discovery of PD-L1's intracellular functions in cancer cells to promote thier survival and metabolism also highlight a mechanism by which tumor cells can gain resistance to cytotoxic therapy and call for a new strategy to target PD-L1. There is therefore a critical need to design, test, and translate new agents that can simultaneously inhibit PD-L1's extracellular and intracellular functions. This application will utilize a new PD-L1 antibody (clone H1A) that can reduce the expression of PD-L1 in tumor cells through disrupting the association of PD-L1 with CMTM6 (a molecule that can stabilize PD-L1 recycling and expression) and subsequently directing PD-L1 for degradation. H1A-induced degradation of PD-L1 may not only disrupt PD-1/PD-L1 interactions due to the loss of PD-L1, thus removing PD-1's suppressive signals in T cells, but also disrupt PD-L1's cell-intrinsic functions within tumor cells and myeloid cells, thereby decreasing tumor resistance to chemotherapy and releasing the immune-stimulatory function of myeloid cells. Thus, H1A antibody may be a good candidate for targeting the dual functions of PD-L1 for cancer therapy. Based on preliminary data, the central hypothesis of this proposal is that intracellular signaling through PD-L1 results in tumor resistance to cytotoxic chemotherapy and limits the immune-stimulatory function of myeloid cells. Thus, targeted agents that result in degradation of PD-L1 and elimination of its intracellular signaling ability represent a novel therapeutic strategy that will both synergize with chemotherapy and improve the immune response. This hypothesis will be tested by pursuing two specific aims: (1) Determine how H1A antibody synergizes with chemotherapy to overcome tumor resistance; (2) Determine how H1A antibody promotes an enhanced T cell response to attack tumors. To further assess the future clinical use of H1A antibody, a fully humanized version of H1A and humanized PD-1 and PD-L1 mice have been produced, which will allow for evaluation of the therapeutic effects of H1A either alone or in combination with chemotherapy and exploration of H1A's new mechanism of action in vivo. The overall impact of the proposed research is high because it will provide a new therapeutic agent that is capable of targeting the dual functions of PD-L1, resulting in improved efficacy of cytotoxic chemotherapy and an enhanced immune response. This strategy represents a significant paradigm shift within the field in terms of how to target immune checkpoint molecules like PD-L1 for future clinical applications.


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 = $327,341 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	5	11/29/2024	NON-COMPETING CONTINUATION	$327,341
														Subtotal = $327,341

Issue Date FY: 2024 ( Subtotal = $345,528 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$18,187
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	4	11/21/2023	NON-COMPETING CONTINUATION	$327,341
														Subtotal = $345,528

Issue Date FY: 2023 ( Subtotal = $356,438 )
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	001	3	3/15/2023	NON-COMPETING CONTINUATION	$29,097
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	3	11/10/2022	NON-COMPETING CONTINUATION	$327,341
														Subtotal = $356,438

Issue Date FY: 2022 ( Subtotal = $356,438 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	2	11/16/2021	NON-COMPETING CONTINUATION	$327,341
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	001	2	4/25/2022	NON-COMPETING CONTINUATION	$29,097
														Subtotal = $356,438

Issue Date FY: 2021 ( Subtotal = $363,713 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	1	11/30/2020	NEW	$363,713
														Subtotal = $363,713

Grand Total All Awards = $1,749,458

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Targeting dual functions of PD-L1 for cancer therapy

Award Number: R01CA256927

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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