Noninvasive interrogation of CD8+ T cell effector function for monitoring early tumor responses to immunotherapy
Haoyi Zhou, … , Zhi Yang, Zhaofei Liu
Haoyi Zhou, … , Zhi Yang, Zhaofei Liu
Published July 5, 2022
Citation Information: J Clin Invest. 2022;132(16):e161065. https://doi.org/10.1172/JCI161065.
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Research Article Oncology

Noninvasive interrogation of CD8+ T cell effector function for monitoring early tumor responses to immunotherapy

Abstract

Accurately identifying patients who respond to immunotherapy remains clinically challenging. A noninvasive method that can longitudinally capture information about immune cell function and assist in the early assessment of tumor responses is highly desirable for precision immunotherapy. Here, we show that PET imaging using a granzyme B–targeted radiotracer named 68Ga-grazytracer, could noninvasively and effectively predict tumor responses to immune checkpoint inhibitors and adoptive T cell transfer therapy in multiple tumor models. 68Ga-grazytracer was designed and selected from several radiotracers based on non-aldehyde peptidomimetics, and exhibited excellent in vivo metabolic stability and favorable targeting efficiency to granzyme B secreted by effector CD8+ T cells during immune responses. 68Ga-grazytracer permitted more sensitive discrimination of responders and nonresponders than did 18F-fluorodeoxyglucose, distinguishing between tumor pseudoprogression and true progression upon immune checkpoint blockade therapy in mouse models with varying immunogenicity. In a preliminary clinical trial with 5 patients, no adverse events were observed after 68Ga-grazytracer injection, and clinical responses in cancer patients undergoing immunotherapy were favorably correlated with 68Ga-grazytracer PET results. These results highlight the potential of 68Ga-grazytracer PET to enhance the clinical effectiveness of granzyme B secretion–related immunotherapies by supporting early response assessment and precise patient stratification in a noninvasive and longitudinal manner.

Authors

Haoyi Zhou, Yanpu Wang, Hongchuang Xu, Xiuling Shen, Ting Zhang, Xin Zhou, Yuwen Zeng, Kui Li, Li Zhang, Hua Zhu, Xing Yang, Nan Li, Zhi Yang, Zhaofei Liu

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Figure 5

PET imaging of 68Ga-grazytracer in mouse models with or without inhibition of immune cell infiltration.

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PET imaging of 68Ga-grazytracer in mouse models with or without inhibiti...
(A) Timeline of PET imaging, anti–PD-1 plus anti–CTLA-4 combinational immunotherapy, and FTY720 treatment in MC38 tumor–bearing mice. (B) Tumor growth curves of MC38 tumor–bearing mice after the indicated treatments: control (PBS), FTY720, anti–PD-1 plus anti–CTLA-4, and anti–PD-1 plus anti–CTLA-4 plus FTY720 (n = 6–9/group). (C and D) Representative PET images (C) and quantified tumor uptake (D) of 18F-FDG on days 0 and 6 in anti–PD-1– plus anti–CTLA-4–treated MC38 tumor–bearing mice with or without FTY720 treatment (n = 8–9/group). (E and F) Representative PET images (E) and quantified tumor uptake (F) of 68Ga-grazytracer on days 0 and 6 in anti–PD-1– plus anti–CTLA-4–treated MC38 tumor–bearing mice with or without FTY720 treatment (n = 8–9/group). (G) Flow cytometric analysis depicting the proportion of NK1.1+ cells, CD4+ T cells, and CD8+ T cells in CD45+ cells in tumors harvested from mice after the indicated treatments (n = 5/group). Tumors are indicated by white arrows in PET images. All numerical data are presented as mean ± SD. *P < 0.05, **P < 0.01, ****P < 0.0001 by 2-way ANOVA (B), 2-tailed paired Student’s t test (D and F), and 2-tailed unpaired Student’s t test (G).