Ma Lucy X, Titmuss Emma, Loree Jonathan M, Jonker Derek J, Kennecke Hagen F, Berry Scott, Couture Felix, Ahmad Chaudhary E, Goffin John R, Kavan Petr, Harb Mohammed, Colwell Bruce, Samimi Setareh, Samson Benoit, Abbas Tahir, Aucoin Nathalie, Aubin Francine, Koski Sheryl, Tu Dongsheng, O'Callaghan Christopher, Chen Eric X
Princess Margaret Cancer Centre, Toronto, Ontario, Canada
BC Cancer - Vancouver, Vancouver, British Columbia, Canada.
J Immunother Cancer. 2024 Dec 4;12(12):e010094. doi: 10.1136/jitc-2024-010094.
Nutritional stress is a mechanism that allows tumor cells to evade the immune system. Arginine (ARG), an amino acid involved in immunomodulation, aids in regulating T-lymphocyte cell activity and the antitumor response. ARG deficiency in the tumor microenvironment can impair T-cell response while ARG supplementation may promote antitumor immune activity. In this exploratory post hoc analysis of the randomized phase II CO.26 trial, we investigated the role of plasma ARG in predicting response to immune checkpoint inhibitors (ICI) in patients with microsatellite stable refractory metastatic colorectal cancer (mCRC).
CO.26 randomized patients with refractory mCRC to durvalumab plus tremelimumab (D+T) versus best supportive care (BSC). Plasma ARG concentrations were determined from pretreatment blood samples using high-performance liquid chromatography-tandem mass spectrometry. The median plasma ARG value was used as a cut-off stratifying patients into ARG-high (≥10 700 ng/mL) versus ARG-low (<10 700 ng/mL) groups. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazard models were used to analyze the prognostic and predictive impacts of ARG on OS.
Of 180 patients enrolled in CO.26, 161 (N=114 treated with D+T and 47 BSC) had pretreatment blood samples for ARG analysis. There were no significant differences in baseline characteristics between patients included in this analysis and the total study patients, or between ARG-high and ARG-low patients. In the BSC arm, the median OS was 3.09 months for ARG-high versus 4.27 months for ARG-low patients (univariable HR 0.89 (0.49-1.65), p=0.72). In the D+T arm, the median OS was 7.62 months for ARG-high versus 5.27 months for ARG-low patients (univariable HR 0.68, (0.48-1.0], p=0.048). In ARG-high patients, D+T significantly improved OS (median OS 7.62 months with D+T vs 3.09 months BSC; HR 0.61 (0.37-0.99), p=0.047; adjusted p=0.042 for interaction). In ARG-low patients there was no OS benefit with D+T (median OS 5.27 months D+T vs 4.27 months BSC; HR 0.87 (0.52-1.46), p=0.61).
High baseline plasma ARG was predictive of improved OS in patients with mCRC treated with D+T. Further investigations are needed to validate ARG as a biomarker. Therapeutic approaches targeting the ARG pathway may augment ICI activity.
NCT02870920.
营养应激是肿瘤细胞逃避免疫系统的一种机制。精氨酸（ARG）是一种参与免疫调节的氨基酸，有助于调节T淋巴细胞细胞活性和抗肿瘤反应。肿瘤微环境中的精氨酸缺乏会损害T细胞反应，而补充精氨酸可能会促进抗肿瘤免疫活性。在这项对随机II期CO.26试验的探索性事后分析中，我们研究了血浆精氨酸在预测微卫星稳定的难治性转移性结直肠癌（mCRC）患者对免疫检查点抑制剂（ICI）反应中的作用。
CO.26将难治性mCRC患者随机分为度伐利尤单抗联合曲美木单抗（D+T）组和最佳支持治疗（BSC）组。使用高效液相色谱-串联质谱法从治疗前的血样中测定血浆精氨酸浓度。血浆精氨酸的中位数用作临界值，将患者分为精氨酸高（≥10700 ng/mL）组和精氨酸低（<10700 ng/mL）组。使用Kaplan-Meier方法估计总生存期（OS），并使用对数秩检验进行比较。Cox比例风险模型用于分析精氨酸对OS的预后和预测影响。
在CO.26试验入组的180例患者中，161例（N = 114例接受D+T治疗，47例接受BSC治疗）有治疗前血样用于精氨酸分析。该分析纳入的患者与整个研究患者之间，以及精氨酸高和精氨酸低的患者之间，基线特征均无显著差异。在BSC组中，精氨酸高的患者中位OS为3.09个月，精氨酸低的患者为4.27个月（单变量HR 0.89（0.49 - 1.65），p = 0.72）。在D+T组中，精氨酸高的患者中位OS为7.62个月，精氨酸低的患者为5.27个月（单变量HR 0.68，（0.48 - 1.0]，p = 0.048）。在精氨酸高的患者中，D+T显著改善了OS（D+T组中位OS为7.62个月，BSC组为3.09个月；HR 0.61（0.37 - 0.99），p = 0.047；交互作用校正p = 0.042）。在精氨酸低的患者中，D+T没有OS获益（D+T组中位OS为5.27个月，BSC组为4.27个月；HR 0.87（0.52 - 1.46），p = 0.61）。
高基线血浆精氨酸可预测接受D+T治疗的mCRC患者OS改善。需要进一步研究以验证精氨酸作为生物标志物。针对精氨酸途径的治疗方法可能会增强ICI活性。
NCT02870920。
