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IL-15 and -21 armored GPC3-specific CAR T cells for children with solid tumors

Award Number: R01CA258866
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/17/2022
PERIOD OF PERFORMANCE END DATE: 10/31/2025

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IL-15 and -21 armored GPC3-specific CAR T cells for children with solid tumors - CAR T cells can induce remarkable antitumor responses in patients with hematologic cancers but have been largely ineffective in patients with solid tumors. Several barriers limit CAR T efficacy in solid malignancies including the limited number of safe solid tumor-specific antigens and an immunosuppressive tumor microenvironment (TME) that lacks supporting stimuli. Furthermore, it remains unknown how CAR T cells influence the evolution of immune escape mechanisms in the human TME. We developed and tested a set of chimeric antigen receptors (CARs) that 1) target glypican-3 (GPC3), a tumor antigen selectively expressed by several pediatric solid tumors but not non-malignant tissues, and 2) co-express interleukin-15 (IL15) and IL21, cytokines that are important for T cell survival, expansion, persistence, and retention of antitumor effector functionality. We found that T cells co-expressing a second generation GPC3-CAR and IL15 (15.GPC3-CAR) have significantly improved expansion, persistence, and antitumor activity compared to GPC3-CAR T cells, and that co-expression of both IL15 and IL21 (15.21.GPC3-CAR) further enhances these properties in preclinical models. Additionally, our preclinical studies showed that 15.21.GPC3-CAR T cells uniquely maintain expression of T cell factor-1, which protects CAR T cells from exhaustion and preserves proliferative capacity following repeated GPC3-mediated activation. Since the safety and efficacy parameters of these cytokine-expressing CAR T cells in humans are unknown, we propose to evaluate 15.GPC3-CAR and 15.21.GPC3-CAR T cells in sequential phase 1 studies using Bayesian Optimal Interval dose escalation in children with relapsed or refractory GPC3-positive solid tumors. Our multidisciplinary team has already generated promising safety and efficacy results treating children with T cells expressing the GPC3-CAR alone. We hypothesize that 15.GPC3-CAR and 15.21.GPC3-CAR T cells will be safe and that co-expression of IL15 with IL21 will enable GPC3-CAR T cells to overcome the inhibitory TME, resulting in robust expansion, persistence, and durable antitumor responses. In Aim 1, we will evaluate the safety of 15.GPC3-CAR and 15.21.GPC3-CAR T cells in children with GPC3-positive solid tumors. In Aim 2, we will determine the in vivo persistence and antitumor activity of CAR T cells. Finally, in Aim 3, through the evaluation of CAR T cell products, peripheral blood samples, and post-infusion tumor biopsies, we will define the transcriptomic and phenotypic profiles of GPC3-CAR T cells, cancer cells, and non- neoplastic stromal cells. We will identify survival programs in CAR T cells and define immune escape mechanisms in the TME using single-cell RNA sequencing, flow cytometry, and COdetection-by-inDEXing. Through the proposed research, we will determine the safety, in vivo expansion and persistence, and antitumor activity of our therapeutic cells. The results will identify survival programs in CAR T cells and immune escape mechanisms in the human TME to provide a blueprint for developing effective measures that boost the efficacy of CAR-based and other immunotherapies for patients with 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: 2026 ( Subtotal = $615,969 )
2026	2026	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Cancer Treatment Research	001	5	2/19/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$615,969
2026	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	002	4	4/3/2026	NON-COMPETING CONTINUATION	$0
2026	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	4	2/18/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $615,969

Issue Date FY: 2025 ( Subtotal = $631,007 )
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	4	12/20/2024	NON-COMPETING CONTINUATION	$567,907
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	001	4	6/6/2025	NON-COMPETING CONTINUATION	$63,100
														Subtotal = $631,007

Issue Date FY: 2024 ( Subtotal = $601,989 )
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	001	3	4/22/2024	NON-COMPETING CONTINUATION	$31,684
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	3	1/9/2024	NON-COMPETING CONTINUATION	$570,305
														Subtotal = $601,989

Issue Date FY: 2023 ( Subtotal = $622,304 )
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	001	2	3/16/2023	NON-COMPETING CONTINUATION	$50,800
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	2	12/7/2022	NON-COMPETING CONTINUATION	$571,504
														Subtotal = $622,304

Issue Date FY: 2022 ( Subtotal = $635,004 )
2022	2022	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	1	1/17/2022	NEW	$635,004
														Subtotal = $635,004

Grand Total All Awards = $3,106,273

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IL-15 and -21 armored GPC3-specific CAR T cells for children with solid tumors

Award Number: R01CA258866

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/17/2022

PERIOD OF PERFORMANCE END DATE: 10/31/2025

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