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The role of antigen binding strength in CAR T cell activity

Award Number: K08CA237868
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/05/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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The role of antigen binding strength in CAR T cell activity - PROJECT SUMMARY/ABSTRACT Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of patients with leukemia, yet robust responses to this modality in solid tumors have been lacking. As a result, most patients with relapsed or refractory solid tumors remain in dire need of alternative therapy. Given the inhospitable solid tumor microenvironment, we are unlikely to achieve robust responses without the most highly potent CAR T cells. My previous studies have demonstrated that CAR T cell potency can be enhanced by increasing the affinity of CAR for its cognate antigen. Further investigation revealed that in particular cytotoxicity was enhanced, whereas T cell survival and central memory (Tcm) differentiation (both important in CAR T clinical persistence and efficacy) were actually impaired in the high affinity CAR T cells. The inverse influence of antigen binding affinity on cytotoxicity and persistence raises questions as to the cellular signaling events underlying these discordant effects. The findings also highlight the possibility that by reversing these decrements in survival and memory in the high affinity cells, CAR T cell potency could be unleashed even further. The central hypothesis to be tested here is that increased CAR affinity results in faster and more sustained activation of downstream T cell signaling pathways, enhancing cytotoxic granule release yet overly engaging signaling molecules such as ERK and Akt, tipping the cellular balance away from survival and memory differentiation and toward cell death. To test the hypothesis, first I will use selected panels of affinity variants to evaluate the relationship between CAR affinity and the activation kinetics of key signaling pathways by quantitative Western blot and phospho-protein flow cytometry. Then using the same panels of affinity variants, I will evaluate the impact of CAR affinity on both cytotoxic granule release using microscopy as well as T cell survival and memory differentiation in vitro using flow cytometry. Lastly, I will identify and evaluate targetable mediators of the survival balance operating in high affinity CAR T cells in vitro and in vivo. To do so, I will compare the affinity variant CAR T cells’ survival and Tcm differentiation in vitro and in vivo in the presence or absence of specific inhibitors of pathways (MEK, Akt, and Fas) that when over-activated can impair T cell survival or memory differentiation. These studies are expected to yield highly potent CAR T cells equipped to address the challenge of solid tumors where both efficient killing and robust persistence are necessary for efficacy. The training plan developed for this proposal is designed to provide me with skills such as advanced microscopy techniques that are necessary to best address the questions raised. Also incorporated into the training plan is mentorship from experts in the CAR field, an advisory committee with special expertise in lymphocyte signaling and imaging, formal didactic experiences in career development, and an overall training environment that will help me to develop into an independent physician- scientist.


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	CHILDREN'S HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Research Manpower	000	6	11/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $178,314 )
2024	2024	CHILDREN'S HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Research Manpower	000	6	6/14/2024	NON-COMPETING CONTINUATION	$178,314
														Subtotal = $178,314

Issue Date FY: 2023 ( Subtotal = $178,314 )
2023	2023	CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Research Manpower	000	5	6/14/2023	NON-COMPETING CONTINUATION	$178,314
														Subtotal = $178,314

Issue Date FY: 2022 ( Subtotal = $178,314 )
2022	2022	CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Research Manpower	000	4	6/30/2022	NON-COMPETING CONTINUATION	$178,314
														Subtotal = $178,314

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	003	2	6/11/2021	NON-COMPETING CONTINUATION	-$5,116
2021	2020	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	000	2	5/21/2021	NON-COMPETING CONTINUATION	-$173,198
2021	2020	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Research Manpower	001	3	5/21/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$173,198
2021	2020	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Research Manpower	004	3	6/11/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$45,362
2021	2019	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	002	1	6/11/2021	NEW	-$40,246
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $178,314 )
2020	2020	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	000	2	6/18/2020	NON-COMPETING CONTINUATION	$178,314
														Subtotal = $178,314

Issue Date FY: 2019 ( Subtotal = $178,314 )
2019	2019	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	000	1	7/5/2019	NEW	$178,314
														Subtotal = $178,314

Grand Total All Awards = $891,570

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The role of antigen binding strength in CAR T cell activity

Award Number: K08CA237868

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/05/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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