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Interrogating the in vivo pharmacokinetics of armored CARs with radiohapten capture

Award Number: R37CA262557
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/07/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Interrogating the in vivo pharmacokinetics of armored CARs with radiohapten capture - Project Summary/Abstract CD19-targeted chimeric antigen receptor (CAR) T cell therapy has shown remarkable treatment effects in B-cell malignancies, but many patients suffer from limited response and CD19-negative tumor relapse. Recently, we demonstrated that next-generation “armored” CAR T cells constitutively expressing the immune-stimulatory molecule CD40 ligand (CD40L) exhibited superior antitumor efficacy in preclinical studies but have not yet been fully explored in the context of CAR antigen-negative tumor relapse. There remains an urgent need for the non-invasive in vivo tracking of transfused T cells to determine their biodistribution, expansion, and functionality and to increase the CAR T cells’ killing capacity in case of imminent treatment failure. To overcome these limitations, we began developing methods for monitoring the in vivo kinetics of CAR T cells based on the concept of immune cell radiohapten capture. We demonstrated for the first time that T cells can be successfully transduced with a DOTA-antibody reporter, the DAbR1, enabling their in vivo tracking via PET and SPECT. In the current proposal, we build on this work and optimize our approach for translation of immune cell radiohapten capture from animals to patients, based on greatly improved components of 1) radiohapten capture reporter scFv C825 with picomolar binding affinity, and 2) optimized radiohaptens, the next- generation Proteus-DOTA (Pr) series suitable for imaging and targeted alpha therapy (TAT). The primary objectives of this study are to develop a clinically applicable PET imaging strategy of CAR T cell trafficking in B- cell malignancies and further study the effect of CD40L on counteracting the immune inhibition in syngeneic models of B-cell malignancies. The secondary objectives are to deliver TAT to enhance T cells’ killing capacity in cases of imminent treatment failure and improve the potency of CAR T cell therapies. We project to achieve our aims by generating second-generation and armored CD 19 CAR T cells expressing cell-surface anchored scFv C825. Syngeneic and immunodeficient xenograft murine models of CD19+ B cell malignancies including antigen-loss variants will be employed. After successful transduction, we will assess in vitro functionality of the CAR and the reporter, as well as radiation toxicity, followed by in vivo functionality, imaging sensitivity, and biodistribution, and develop an armored CAR T cell-based theranostic approach with the novel pair [86Y]YPr/[225Ac]AcPr. Finally, as a prerequisite to clinical translation of this novel platform, we will conduct studies using human second-generation and armored CAR T cells in clinically relevant xenograft models. The availability of such a single platform would provide crucial information for safer, more effective clinical trials. The aims thus have immediate translational relevance for our current clinical CD19 CAR T studies and other planned CAR T cell therapy trials.


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 = $529,244 )
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	004	6	6/30/2025	NON-COMPETING CONTINUATION	$529,244
2025	2024	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	001	5	4/25/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$155,995
2025	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Detection and Diagnosis Research	000	4	4/25/2025	NON-COMPETING CONTINUATION	-$155,995
2025	2024	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	003	5	5/13/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$387,176
2025	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Detection and Diagnosis Research	002	4	5/13/2025	NON-COMPETING CONTINUATION	-$387,176
														Subtotal = $529,244

Issue Date FY: 2024 ( Subtotal = $561,789 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Detection and Diagnosis Research	000	4	6/12/2024	NON-COMPETING CONTINUATION	$561,789
														Subtotal = $561,789

Issue Date FY: 2023 ( Subtotal = $668,696 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Detection and Diagnosis Research	000	3	6/7/2023	NON-COMPETING CONTINUATION	$668,696
														Subtotal = $668,696

Issue Date FY: 2022 ( Subtotal = $551,690 )
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Detection and Diagnosis Research	000	2	6/16/2022	NON-COMPETING CONTINUATION	$551,690
														Subtotal = $551,690

Issue Date FY: 2021 ( Subtotal = $523,072 )
2021	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Detection and Diagnosis Research	000	1	7/7/2021	NEW	$523,072
														Subtotal = $523,072

Grand Total All Awards = $2,834,491

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Interrogating the in vivo pharmacokinetics of armored CARs with radiohapten capture

Award Number: R37CA262557

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/07/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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