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Activating Native Tumor Immunity with IL-33 Armored CARs

Award Number: R01CA271553
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Activating Native Tumor Immunity with IL-33 Armored CARs - ABSTRACT Unlike liquid cancers, current CAR T cell immunotherapies have little effect against solid cancers, largely due to the immunosuppressive nature of the tumor microenvironment. The race between administered CAR T cells and tumor associated cells to kill off and/or neutralize the other is tipped heavily in favor of the tumor. Heterogeneous tumors or tumors able to shed or downregulate CAR-targeted antigens can also escape elimination by functional CAR T cell effectors. We recently found that CAR T cells delivery of dual cytokines can enlist and activate endogenous T cells, NK cells and myeloid cells to mount an effective anti-tumor immune response. Further investigation revealed that perforin and IFNγ are dispensable in CAR T cells, supporting an accessory role for CAR T cells in mobilizing endogenous immune cells to ultimately control tumor growth. CAR T cell-mediated dual cytokine delivery was effective in controlling tumor growth with 3 different CAR T cell constructs and 4 in vivo tumor models: primary and metastatic melanoma and primary colon cell carcinoma mouse models, and importantly was impervious to antigen loss. This suggests that the dual cytokine platform has potential for universal application against multiple solid tumor types. In this application, we hypothesize that CAR T cell delivery of dual cytokines has broad application because it counteracts immunosuppressive innate and adaptive immune cells to elicit a broad endogenous anti-tumor response independent of CAR effector potential. We will test this hypothesis by identifying CAR T cell survival and distribution dynamics (Aim 1), identify the common and tumor-specific changes in immunosuppressive, immunostimulatory and effector leukocyte populations isolated from poorly and strongly immunogenic tumors pre- and post-CAR cytokine treatment (Aim 2), and determine their roles in activating endogenous tumor immunity (Aim 3). The cellular and mechanisms identified will support further improvement and clinical translation of the Super2+IL-33 platform with various CAR targeting constructs for CAR T cell therapies for solid tumors.


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 = $575,420 )
2025	2025	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Treatment Research	000	3	5/19/2025	NON-COMPETING CONTINUATION	$575,420
														Subtotal = $575,420

Issue Date FY: 2024 ( Subtotal = $546,511 )
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Treatment Research	000	2	5/29/2024	NON-COMPETING CONTINUATION	$546,511
														Subtotal = $546,511

Issue Date FY: 2023 ( Subtotal = $573,520 )
2023	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Treatment Research	000	1	5/17/2023	NEW	$573,520
														Subtotal = $573,520

Grand Total All Awards = $1,695,451

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Activating Native Tumor Immunity with IL-33 Armored CARs

Award Number: R01CA271553

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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