@misc{oai:repo.qst.go.jp:00072449,
 author = {Xie, Lin and Zhang, Yiding and Jiang, Cuiping and Wakizaka, Hidekatsu and Kumata, Katsushi and Nengaki, Nobuki and Zhang, Ming-Rong and 謝 琳 and 張 一鼎 and 脇坂 秀克 and 熊田 勝志 and 念垣 信樹 and 張 明栄},
 month = {Sep},
 note = {Background and Objectives: Defining biomarkers that reliably monitor antitumor responses represents a crucial challenge, due to the complexity of continuous crosstalk between tumor cells and host immune system during immunotherapeutic manipulation [1]. Whole-body imaging with a broad view can aid this exploration, and attempt had been started by developing novel PET probes derived from indoleamine-2,3-dioxygenase (IDO1) checkpoint inhibitor [2]. Here, we addressed further this problem by first validating a promising platform imaging biomarker—the 11C-L-1MTrp-PET— in melanoma mice with the presence or absence of antitumor immune responses.
Methods: The IDO1-targeting combination immunotherapeutic models were established in immunocompetent C57BL/6J mice by s.c. transplantation of B16F10 melanoma cells, then treated with IDO1 inhibitor L-1MTrp combination with chemotherapeutic agents cyclophosphamide (CPA) or paclitaxel (PTX). Treatment responses were defined through quantifying the specific growth rate (SGR; %/d) of tumors.11C-L-1MTrp with PET/CT, was performed to capture pharmacokinetic imaging during treatment-induced immune editing. Biodistribution, autoradiography, and histopathology were conducted to confirm the results of whole-body PET. Receiver operating characteristic (ROC) curve analysis was performed to define an optimal cutoff for discriminating between responsive and unresponsive immune conditions.
Results: The activated antitumor response, a progression-free SGR, was proved in melanoma mice treated with L-1MTrp and CPA, compared with L-1MTrp and PTX. Whole-body PET/CT exhibited a high accumulation of 11C-L-1MTrp in mesenteric lymph nodes (MLN) and epididymis (Fig 1), in the mice with L-1MTrp and CPA therapy(MLN 9.46 ± 0.33 %ID/g; epididymis 11.36 ± 0.43 %ID/g, at 75 min), but not in the placebo mice (mLN 3.55 ± 0.32 %ID/g; epididymis 3.21 ± 0.34 %ID/g) or the unresponsive mice (MLN 4.51 ± 0.41 %ID/g; epididymis 4.92 ± 0.83 %ID/g) with L-1MTrp and PTX therapy. Biodistribution and autoradiography confirmed the unforeseen PET pharmacokinetic imaging. Immunohistochemistry verified same expression pattern of IDO1 in MLN and epididymis. Empirical cutoff in mLN and epididymis were identified that discriminated with 100% sensitivity and specificity between responsive and unresponsive conditions in the two chemo-immunotherapeutical models strategies. Tracking with 11C-L-1MTrp PET the longitudinal efficacy of L-1MTrp and CPA, the cutoff of MLN provided early on-treatment indicator of response with a specificity of 97.92 %, and the cutoff of epididymis resulted in a sensitivity of 100% as a predictive index of immune exhaustion.
Conclusion: Immune-checkpoint protein IDO1 combination immunotherapy edited pharmacokinetics of inhibitor L-1MTrp and host immunity in melanoma mice. 11C-L-1MTrp PET as a sensitive platform imaging biomarker, including a primary biomarker of MLN and secondary biomarker of epididymis, may carry out global and reliable identification of the IDO1 targeting antitumor responses, with prospective near-term clinical application.
\nReferences: [1]. Pardoll DM. Nature Rev. Cancer. 2012, 12, 252. [2] Xie, L. et al. Sci. Rep.2015, 5,16417.
\nFigure1. PET imaging of 11C-L-1MTrp in B16F10 bearing C57BL/6J mice treated with either placebo (+PBS) or L-1MTrp combination with cyclophosphamide (CPA) / paclitaxel (PTX). White circles indicate tumors, blue triangles indicate mesenteric lymph nodes, and green triangles indicate epididymis., 2017 World Molecular Imaging Congress(WMIC2017)},
 title = {Identifying antitumor responses of IDO1-targeting combination immunotherapy through 11C-L-1MTrp based PET platform},
 year = {2017}
}