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Use of a Nano-Enabled Platform for Pancreatic Cancer Immunotherapy

Award Number: R01CA247666
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Use of a Nano-Enabled Platform for Pancreatic Cancer Immunotherapy - The use of nano-enabled chemotherapy to trigger an immune response to pancreatic ductal adenocarcinoma (PDAC) introduces a novel approach for overcoming robust barriers to immunotherapy, including poor immunogenicity, low neoantigen burden, stromal interference (“T-cell exclusion”), overexpression of indoleamine 2,3-dioxygenase (IDO-1), and the immune privileged environment of the liver favoring metastatic spread. Our preliminary data show that lipid-bilayer coated mesoporous silica nanoparticles (silicasomes) provide an effective platform for inducing immunogenic cell death (ICD) by delivering prescreened chemotherapeutic agents to the PDAC site. ICD promotes the presentation of endogenous tumor antigens cells, raising the hypothesis that ICD offers a promising endogenous vaccination approach to generate a “hot” tumor microenvironment (TME) that can be propagated by co-delivery of drugs interfering in regionally overexpressed immunosuppressive pathways. These pathways can be targeted by inhibitors of IDO-1, CXCR4 (T-cell exclusion) and glycogen synthase kinase 3 (which controls PD-1 expression). We also propose that metastatic spread can be reduced by ICD-induced memory T-cells and delivery of “stimulator of interferon genes” (STING) agonists to tolerogenic antigen presenting cells in the liver. The long-term goal of our interdisciplinary efforts is to develop a chemo-immunotherapy platform for delivery of ICD stimuli by the silicasome contemporaneous with inhibitors of immune checkpoint and T-cell exclusion pathways (CXCR4). The objectives include the use of innovative drug loading and cholesterol-conjugated prodrugs to synthesize silicasomes that can be used to obtain the best synergy between ICD stimuli and inhibitors of immunosuppressive pathways in orthotopic and genetic engineered PDAC models. This requires research discovery into the mechanistic basis of synergy between ICD and regional immune escape pathways. We will use an integrin-targeting, tumor-penetrating iRGD peptide to enhance drug delivery by a transcytosis pathway. We will also construct polymeric nanocarriers to deliver STING agonists for preventing metastatic spread to the liver. The rationale is that the use of an ICD approach to generate a “hot” tumor environment will facilitate combination immunotherapy with improvement of PDAC mortality. We plan to test our hypothesis by pursuing the following specific aims: Aim 1: To develop a nano-enabled chemo-immunotherapy platform for PDAC that utilizes an endogenous (ICD-mediated) treatment approach plus interference in regionally overexpressed immune checkpoint pathways to generate a “hot” tumor environment. Aim 2: To enhance the immunotherapy impact of the ICD platform by using integrin-targeting, tumor-penetrating iRGD peptides and developing a silicasome that interferes in T-cell exclusion in the stroma through the delivery of CXCR4 inhibitors. Aim #3: To reprogram the immune suppressive effects of liver APC by STING nanoparticles that promote eradication of PDAC metastases by the memory T-cells generated by ICD-inducing silicasomes.


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 = $0 )
2026	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	5	12/2/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $479,283 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	5	6/20/2024	NON-COMPETING CONTINUATION	$479,283
														Subtotal = $479,283

Issue Date FY: 2023 ( Subtotal = $512,817 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	4	6/7/2023	NON-COMPETING CONTINUATION	$512,817
														Subtotal = $512,817

Issue Date FY: 2022 ( Subtotal = $529,313 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	3	6/28/2022	NON-COMPETING CONTINUATION	$529,313
														Subtotal = $529,313

Issue Date FY: 2021 ( Subtotal = $553,064 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	001	2	6/3/2021	NON-COMPETING CONTINUATION	$553,064
2021	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Treatment Research	000	1	4/13/2021	NEW	$0
														Subtotal = $553,064

Issue Date FY: 2020 ( Subtotal = $553,064 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Treatment Research	000	1	6/9/2020	NEW	$553,064
														Subtotal = $553,064

Grand Total All Awards = $2,627,541

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Use of a Nano-Enabled Platform for Pancreatic Cancer Immunotherapy

Award Number: R01CA247666

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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