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Image-guided adaptable CAR T cell therapy for solid tumors

Award Number: R21CA299243
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/09/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Image-guided adaptable CAR T cell therapy for solid tumors - PROJECT SUMMARY Despite promising results in treating B cell malignancies, over 50% of patients undergoing chimeric antigen receptor (CAR) T cell therapy experience tumor relapse, and CAR T cells have not consistently shown effectiveness against solid tumors. Antigen escape, T cell exhaustion, and severe toxicities remain major obstacles. This proposal addresses these challenges by developing an image-guided, universal, adaptable CAR (A-CAR) system comprising a tumor-targeting adaptor molecule fused with a C-terminal tag and a tag-specific CAR on T cells. Our stepwise approach to image-guided CAR T cell therapy involves: (1) Imaging: PET assessment of adaptor biodistribution using radiolabeled VHH adaptors; (2) Treatment: a single infusion of autologous tag-specific CAR T cells with optimized VHH adaptors that coat tumor cells for CAR T recognition; and (3) Assessment: monitoring tumor response and CAR T distribution via ¹⁸F-FDG and ⁶⁸Ga-DOTATATE PET/CT. The clinically approved radiotracer ⁶⁸Ga-DOTATATE tracks CAR T cell expansion and activity at on- and off-tumor sites through binding to somatostatin receptor 2 (SSTR2) co-expressed on CAR T cells. The high specificity, affinity, and favorable kinetics of VHHs make them ideal for PET imaging and as CAR T cell adaptors, enabling non-invasive detection of antigen expression, patient selection, and prediction of homing sites and offtumor toxicity prior to treatment. This project comprehensively investigates VHHs as CAR T adaptors, including pharmacokinetic and biodistribution characterization, optimization of delivery (intermittent cyclic tumor tagging vs. continuous infusion) and dosing, and the potential to mitigate T cell exhaustion and overcome antigen escape through multi-antigen targeting. Mouse xenograft and syngeneic tumor models are essential for this work, as they are the only systems in which VHH adaptor biodistribution, CAR T cell trafficking, tumor targeting, and toxicity can be evaluated together in a living organism. These in vivo models enable optimization of adaptor and CAR T dosing, assessment of antigen escape and exhaustion under physiological conditions, and validation of PET imaging as a predictive tool — none of which are achievable in cell culture. By refining VHH and CAR T delivery guided by quantitative imaging, we seek to enhance efficacy and minimize off-tumor toxicity, with the ultimate goal of advancing A-CAR therapy against solid cancers.


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 = $415,257 )
2026	2026	THE METHODIST HOSPITAL RESEARCH INSTITUTE	6565 FANNIN ST STE D200	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	000	1	6/11/2026	NEW	$415,257
														Subtotal = $415,257

Grand Total All Awards = $415,257

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Image-guided adaptable CAR T cell therapy for solid tumors

Award Number: R21CA299243

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/09/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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