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Improving CAR T cell therapy for brain tumors using immune competent models

Award Number: R00CA256262
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Improving CAR T cell therapy for brain tumors using immune competent models - PROJECT SUMMARY/ABSTRACT The overall objective of this study is to engineer a potent CAR T cell therapy for high grade glioma (HGG), a subgroup of brain tumors for which outcomes remain poor. CAR T cell therapy is an innovative technology based on adoptive transfer of antigen-specific T cells engineered to elicit a clinically effective and specific immune response against tumor cells. Early clinical studies in HGG patients demonstrated safety of CAR T cell therapy for brain tumors; yet, only limited benefits were observed. Lack of efficacy is most likely multifactorial and include heterogenous antigen expression, limited homing to and penetration of tumors, T cell exhaustion and limited persistence, as well as the immunosuppressive tumor microenvironment (TME). Therefore, the central hypothesis of this proposal is that optimized design and additional genetic modifications of CAR T cells will improve their antitumor effects, and that these interventions will be evaluated in immune competent mouse models that closely mimic human disease. Three interrelated research aims are proposed to test this hypothesis and the rationale of each is outlined below. First, CAR design has to be optimized and evaluated in immune competent glioma models. In Aim 1, I will generate CAR T cells containing different co- stimulatory domains (CD28.ζ, 41BB.ζ, CD28.mutζ, and 41BB.mutζ), and compare their activity in vitro and in vivo. Second, a genome wide screen in primary T cells has identified key regulators of T cell activation post T- cell receptor (TCR) stimulation. Identified genes belong to molecules that regulate cell cycle, proliferation, and downstream TCR signaling including SOCS1, RASA2, or CBLB. In Aim 2, I will therefore explore if CRISPR- Cas9 mediated silencing of Socs1, Rasa2, and/or Cblb enhances the effector functions of CAR T cells. The independent Aim 3 will then explore a dual CAR targeting approach in which I will not only target glioma cells but also immunosuppressive cells within the glioma microenvironment. These studies are focused on tumor associated macrophages (TAMs), since they are abundantly present in gliomas and play a critical role in shaping the TME. To support the feasibility of this project, I have adapted the well-established immune competent GL261 glioma model to study CAR T cell therapies targeting the relevant tumor antigen B7-H3, which is not only expressed by GL261 cells but also in a broad range of pediatric and adult brain tumors. In addition, my preliminary studies indicate that `prototype' B7- H3 CAR T-cells readily recognize and kill GL261 cells in vitro and have antitumor activity in vivo, highlighting that the developed model is well suited for the proposed aims of this project. State of the art technique will be used in all three Aims to not only study the function and in vivo fate of CAR T-cells, but also their antitumor activity, and how CAR T-cells interact with glioma- infiltrating immune cells. Completion of this study will define the most optimal CAR design that best controls HGG tumors and persists longer in the context of inflammatory brain tumors. Additionally, results will illustrate if targeting TAMs will overcome the suppressive effects of TME on B7-H3 CAR T cells.


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 = -$1,004 )
2026	2025	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Cancer Treatment Research	000	5	4/17/2026	NON-COMPETING CONTINUATION	-$1,004
														Subtotal = -$1,004

Issue Date FY: 2025 ( Subtotal = $215,029 )
2025	2025	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Cancer Treatment Research	000	5	12/16/2024	NON-COMPETING CONTINUATION	$190,128
2025	2025	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Cancer Treatment Research	001	5	6/12/2025	NON-COMPETING CONTINUATION	$24,901
														Subtotal = $215,029

Issue Date FY: 2024 ( Subtotal = $282,973 )
2024	2024	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Cancer Treatment Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$24,901
2024	2024	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Cancer Treatment Research	000	4	12/15/2023	NON-COMPETING CONTINUATION	$224,100
2024	2023	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Cancer Treatment Research	002	3	4/23/2024	EXTENSION WITH OR WITHOUT FUNDS	$33,972
														Subtotal = $282,973

Issue Date FY: 2023 ( Subtotal = $249,001 )
2023	2023	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Cancer Treatment Research	001	3	5/30/2023	EXTENSION WITH OR WITHOUT FUNDS	$0
2023	2023	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Cancer Treatment Research	000	3	12/23/2022	EXTENSION WITH OR WITHOUT FUNDS	$249,001
														Subtotal = $249,001

Grand Total All Awards = $745,999

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Improving CAR T cell therapy for brain tumors using immune competent models

Award Number: R00CA256262

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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