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Longitudinal PET imaging demonstrates biphasic CAR T cell responses in survivors
Yogindra Vedvyas, … , John Babich, Moonsoo M. Jin
Yogindra Vedvyas, … , John Babich, Moonsoo M. Jin
Published November 17, 2016
Citation Information: JCI Insight. 2016;1(19):e90064. https://doi.org/10.1172/jci.insight.90064.
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Research Article Immunology Therapeutics

Longitudinal PET imaging demonstrates biphasic CAR T cell responses in survivors

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Abstract

Clinical monitoring of adoptive T cell transfer (ACT) utilizes serial blood analyses to discern T cell activity. While useful, these data are 1-dimensional and lack spatiotemporal information related to treatment efficacy or toxicity. We utilized a human genetic reporter, somatostatin receptor 2 (SSTR2), and PET, to quantitatively and longitudinally visualize whole-body T cell distribution and antitumor dynamics using a clinically approved radiotracer. Initial evaluations determined that SSTR2-expressing T cells were detectable at low densities with high sensitivity and specificity. SSTR2-based PET was applied to ACT of chimeric antigen receptor (CAR) T cells targeting intercellular adhesion molecule-1, which is overexpressed in anaplastic thyroid tumors. Timely CAR T cell infusions resulted in survival of tumor-bearing mice, while later infusions led to uniform death. Real-time PET imaging revealed biphasic T cell expansion and contraction at tumor sites among survivors, with peak tumor burden preceding peak T cell burden by several days. In contrast, nonsurvivors displayed unrelenting increases in tumor and T cell burden, indicating that tumor growth was outpacing T cell killing. Thus, longitudinal PET imaging of SSTR2-positive ACT dynamics enables prognostic, spatiotemporal monitoring with unprecedented clarity and detail to facilitate comprehensive therapy evaluation with potential for clinical translation.

Authors

Yogindra Vedvyas, Enda Shevlin, Marjan Zaman, Irene M. Min, Alejandro Amor-Coarasa, Spencer Park, Susan Park, Keon-Woo Kwon, Turner Smith, Yonghua Luo, Dohyun Kim, Young Kim, Benedict Law, Richard Ting, John Babich, Moonsoo M. Jin

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Figure 1

Expression of human SSTR2 by lentivirus vector in T cells.

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Expression of human SSTR2 by lentivirus vector in T cells.
(A) A schemat...
(A) A schematic of the lentivirus vector encoding human SSTR2 is shown. LTR, long terminal repeat; SD, splice donor; SA, splice acceptor; EF1α, elongation factor 1α promoter; ψ+, encapsidation signal. Histograms show the level of SSTR2-specific antibody binding to wild-type Jurkat T cells (0%, top) and Jurkat T cells transduced with increasing virus titers. Percentages of SSTR2-positive cells are indicated. (B) Level of SSTR2-specific antibody binding to SSTR2-transduced Jurkat T cells with and without preincubation with 1 μM octreotide (37°C, 30 minutes). The numbers denote mean fluorescence intensity. (C) DOTATOC uptake by SSTR2-transduced and wild-type Jurkat T cells versus input DOTATOC concentration is shown. A first-order Langmuir isotherm equation was used to fit the data and to find the equilibrium dissociation constant (Kd). Confidence interval of Kd is shown in parentheses. (D) DOTATOC uptake at 37°C and 4°C by SSTR2-transduced and wild-type Jurkat T cells is shown via Scatchard plot. Predicted Kd is shown. Data shown are from 3 independent experiments. CPM, counts per minute.

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