Abstract 1707: Longitudinal and quantitative imaging of the localization, expansion, and contraction of tumor targeted adoptively transferred T cells
Authors: Yogindra Vedvyas, Enda Shevlin, Marjan Zaman, Irene M. Min, Moonsoo M. Jin
Journal: Cancer Research (2017)

Abstract Introduction: Current methodologies for monitoring adoptive cell transfer (ACT) rely on soluble markers and T cell quantity in serum reflecting mixed responses of T cell efficacy or toxicity. Quantitative, longitudinal T cell visualization can directly probe T cell distribution, expansion, and off-tumor localization, and provide rational to predict therapy successes or failures. To enable real-time PET imaging of adoptively transferred T cells in a manner directly translatable to clinics, we utilized a genetic reporter, somatostatin receptor 2 (SSTR2) and a clinically approved radiotracer to quantitatively and longitudinally visualize whole body T cell distribution and anti-tumor dynamics. SSTR2 imaging was also applied to chimeric antigen receptor (CAR) T cells in a setting of solid cancer. Methods: We developed subcutaneous tumors with a mixture of SSTR2 positive and negative Jurkat T cells, ranging from 0 to 100%. From this model and PET/CT imaging of SSTR2 radiotracer uptake, diagnostic performance of our imaging technique was rigorously defined. To apply SSTR2 imaging to CAR T cells, a new lentivirus vector was designed to allow dual expression of SSTR2 and CAR. Longitudinal PET/CT and luminescence imaging was performed to concurrently measure the rate of tumor growth/killing and T cell expansion and contraction. Blood was also collected to correlate serum cytokines with T cell distribution at on- and off-tumor sites. Histology was performed to confirm the validity of SSTR2 imaging of CAR T cells and relating it to T cell activity. Results: Our T cell imaging technique was found to provide 1% limit of detection (one T cell in one hundred neighboring cells or ~4x106 cell/cm3 in solid tissues) with 95% specificity and 87% sensitivity. When applied to CAR T cells in solid cancer, a biphasic T cell expansion and contraction was observed in survivors where a temporal change of T cell density closely followed the change in tumor burden with some time delay. In contrast, nonsurvivors displayed unrelenting increases in tumor and T cell burden, indicating that tumor growth was outpacing T cell killing. Cytokine release syndrome indicated by weight loss and elevated proinflammatory cytokines was also apparent in a cohort of nonsurvivors. Conclusion: Our study is the first high quality and quantitative, longitudinal imaging of T cells, correlating T cell dynamism with therapy and toxicity responses in subjects. Correlative changes in cytokines and T cell density can be further developed for early prediction of the onset of cytokine release syndrome as well as for screening adjuvant therapies to augment CAR T cell efficacy against solid cancer. Owing to the use of a human gene and FDA-approved radiotracer, our imaging technique can be directly applicable to CAR T cells and other T cell based therapy. We are currently preparing for a phase I clinical study for real-time imaging CD19 CAR T cells in patients. Citation Format: Yogindra Vedvyas, Enda Shevlin, Marjan Zaman, Irene M. Min, Moonsoo M. Jin. Longitudinal and quantitative imaging of the localization, expansion, and contraction of tumor targeted adoptively transferred T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1707. doi:10.1158/1538-7445.AM2017-1707