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Innovative Research for Cancer Nanotechnology (IRCN) for Enhancing Melanoma-specific Immune Responses by the Rational Design of Spherical Nucleic Acids

Award Number: R01CA257926
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/14/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Innovative Research for Cancer Nanotechnology (IRCN) for Enhancing Melanoma-specific Immune Responses by the Rational Design of Spherical Nucleic Acids - PROJECT SUMMARY/ABSTRACT This research will utilize spherical nucleic acid (SNA) nanostructures to develop effective, structure-informed vaccines for advanced melanoma. Traditional treatments (i.e. chemotherapy or radiation) are less successful for melanoma because of difficulties in discerning melanoma cells phenotypically. Immunotherapeutics must ensure that melanoma—with a high mutational burden—cannot easily evade the immune system. SNAs can function as robust cancer vaccines through the precise control over the presentation of multiple melanoma-associated targets to immune cells which lowers its potential for immune evasion. SNAs are composed of a nanoparticle core with a dense radial shell of nucleic acids. When synthesized using immunostimulatory “adjuvant” oligonucleotides, SNAs induce immune responses. Indeed, this adjuvant only structure demonstrates the enhanced responses generated from a 3D structure compared to linear adjuvant and forms the basis of an ongoing Phase 1b/2 clinical trial. We have exploited the ease of chemical synthesis and modular architecture of SNAs, and synthesized them to include both adjuvant and a single tumor-associated peptide (“antigen”). These structures enhance antitumor responses and provide long-term protective immunity in model systems, and in particular, there is a strong relationship between vaccine structure and efficacy. In our proposed work, we aim to develop SNA vaccines against melanoma by precisely incorporating and presenting multiple immunostimulatory cues to the immune system. SNAs will be synthesized with multiple clinically-relevant melanoma antigens (MHC-I and -II restricted, tumor-associated, neoantigens), with structural variations in how the adjuvant and antigen are presented. Control over structure, combined with in vitro and in vivo evaluations of immunostimulation, will elucidate structure-activity relationships that will inform the future of cancer vaccine design. Using structure to control the presentation of multiple immune system cues has the power to elevate immune responses to melanoma and improve clinical outcomes. In Aim 1, we will synthesize SNAs containing multiple antigens and varied stabilities to enhance antigen-specific T cell responses. We will analyze their uptake by immune cells, subcellular trafficking of the SNA components, and kinetics of activation of multiple pathways (e.g. antigen presentation, co-stimulatory marker expression). In Aim 2, we will compare different administration routes and analyze in vivo biodistribution and uptake kinetics, as well as the antigen-specific immune responses raised by SNAs in immunocompetent mice. We will assess raised responses after delivery of SNAs containing human antigens to humanized mice and patient specimens. In Aim 3, we will evaluate SNA antitumor efficacy in vivo alone and in combination with immune checkpoint blockade, and identify SNAs as candidates for further preclinical studies and clinical translation. Significantly, this approach will generate a structure-based understanding of SNA performance as vaccines, and improve immunotherapy by generating a breadth of T cell responses with superior efficacies.


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 = $510,958 )
2026	2026	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	5	3/4/2026	NON-COMPETING CONTINUATION	$510,958
														Subtotal = $510,958

Issue Date FY: 2025 ( Subtotal = $513,840 )
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	4	3/3/2025	NON-COMPETING CONTINUATION	$462,457
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	001	4	7/7/2025	NON-COMPETING CONTINUATION	$51,383
														Subtotal = $513,840

Issue Date FY: 2024 ( Subtotal = $490,839 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	002	3	4/17/2024	NON-COMPETING CONTINUATION	$25,835
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	001	3	3/6/2024	NON-COMPETING CONTINUATION	$465,004
2024	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	2	3/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $490,839

Issue Date FY: 2023 ( Subtotal = $508,916 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	2	9/8/2023	NON-COMPETING CONTINUATION	$508,916
														Subtotal = $508,916

Issue Date FY: 2022 ( Subtotal = $521,890 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	1	3/14/2022	NEW	$521,890
														Subtotal = $521,890

Grand Total All Awards = $2,546,443

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Innovative Research for Cancer Nanotechnology (IRCN) for Enhancing Melanoma-specific Immune Responses by the Rational Design of Spherical Nucleic Acids

Award Number: R01CA257926

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/14/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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