给免疫治疗“减毒增效”的辅助药物（八）--时辰给药

几项回顾性研究表明，在下午四点半前把icb免疫治疗药物全部输注完，疗效更好。
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7 m6 B/ m3 r9 h! f5 F1、《Association of circadian timing of initial infusions of immune checkpoint inhibitors with survival in advanced melanoma》
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0 D8 ?8 j; V0 f' @- h! c“Aims: Chronomodulation of immune checkpoint inhibitors (ICIs) is not well understood. The authors evaluated the circadian timing of initial ICI infusions. Patients & methods: A retrospective cohort study of patients with advanced melanoma (n = 121) was conducted. Results: Exclusive afternoon timing of the first four infusions was associated with worse overall survival (5.5 vs 24.9 months; p < 0.001) and progression-free survival (3.3 vs 7.6 months; p = 0.009) on Kaplan-Meier curves. In multivariable Cox analysis, the rate of overall survival was lower in patients who received all first four ICI infusions in the afternoon versus patients who received ≥1 of the first four infusions in the morning (hazard ratio: 2.4; p = 0.004). Conclusion: Deliberate morning scheduling for the first several ICI treatments may improve patient-centered outcomes.”

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; l# K: T- U3 Q( {2、《Effect of immunotherapy time-of-day infusion on overall survival among patients with advanced melanoma in the USA (MEMOIR): a propensity score-matched analysis of a single-centre, longitudinal study》
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“Between Jan 1, 2012, and Dec 31, 2020, 481 patients with melanoma received treatment with immune checkpoint inhibitors at the study centre, of whom 299 had stage IV disease and were included in this study; median follow-up was 27 months (IQR 14 to 47). In the complete unmatched sample, 102 (34%) patients were female and 197 (66%) were male, with a median age of 61 years (IQR 51 to 72). Every additional 20% of infusions of immune checkpoint inhibitors received after 1630 h (among all infusions received by a patient) conferred an overall survival hazard ratio (HR) of 1·31 (95% CI 1·00 to 1·71; p=0·046). A propensity score-matched analysis of patients who did (n=73) and did not (n=73) receive at least 20% of their infusions of immune checkpoint inhibitors after 1630 h (54 [37%] of 146 patients were women and 92 [63%] were men, with a median age of 58 years [IQR 48 to 68]) showed that having at least 20% of infusions in the evening was associated with shorter overall survival (median 4·8 years [95% CI 3·9 to not estimable] vs not reached; HR 2·04 [1·04 to 4·00; p=0·038]). This result remained robust to multivariable proportional hazards adjustment with (HR 1·80 [1·08 to 2·98; p=0·023]) and without (2·16 [1·10 to 4·25; p=0·025]) inclusion of the complete unmatched study sample. The most common adverse events were colitis (54 [18%] of 299 patients), hepatitis (27 [9%]), and hypophysitis (15 [5%]), and there were no treatment-related deaths.”

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3、《Clinical outcomes by infusion timing of immune checkpoint inhibitors in patients with advanced non-small cell lung cancer》

. W8 J4 ~/ p, F! E$ O8 X( u“180 patients were included, 77% received ICI as second- or further-line (median of 12 infusions/patient). The median age was 65 years (IQR 57-70), 112 patients (62%) were male, 165 (92%) were current or former tobacco smokers, 140 (78%) had performance status (PS) 0 or 1, 26 (14%) were on steroid therapy at ICI initiation. Histology was non-squamous for 139 (77%), the median number of metastatic sites was 3, and 33% had brain metastases. Patients who received at least 20% of ICI infusions after 16:30h (65 out of 180, 36%) had a statistically significant shorter median PFS as compared with patients receiving less than 20% of infusions in the evening (4.9 vs 9.4 months, log-rank p = 0.020), while numerical but not statistical shorter OS was observed (14.0 vs 26.2 months, log-rank p = 0.090). In the multivariate analysis, receiving at least 20% of evening infusions did not significantly increase the risk of death, while PS and line of treatment were significantly correlated with the OS. On the contrary, a proportion of ICI administration after 16:30h ≥20% conferred an HR for the PFS of 1.44 (95% CI: 1.01-2.05, p = 0.043), but this prognostic effect was not found when including in the model the total number of ICI infusions received (HR 1.20, 95% CI: 0.83-1.75, p = 0.329).”


4、《Association Between Time-of-Day of Immune Checkpoint Blockade Administration and Outcomes in Metastatic Renal Cell Carcinoma》
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  J. q" k% z% e# s+ @, c9 R7 |0 A“Methods: Data from patients with mRCC who received nivolumab or nivolumab/ipilimumab, in first- or second-line were retrospectively collected. Patients who received < 20% of infusions after 16:30 were assigned to the early TOI sub-cohort, while the rest were assigned to the late TOI sub-cohort. Clinical outcomes were compared across the 2 groups.
" ~8 v2 K0 V5 S, e  A# M. fResults: Among 135 patients included, 89 (65.9%) and 46 (34.1%) were assigned to early and late TOI sub-cohorts, respectively. Baseline characteristics were comparable across the 2 sub-cohorts. Objective response rate (ORR) was 36.0% with early TOI versus 29.5% with late TOI (P = .157). Median time to treatment failure (TTF) was 9.5 months in the early TOI sub-cohort versus 4.6 months in the late TOI sub-cohort with a hazard ratio (HR) of 1.405 (95% CI, 0.919-2.149; P = .11) in univariate analysis and 1.694 (95% CI, 1.064-2.698; P = .026) in multivariate analysis. Higher cut offs allocating patients into the late TOI sub-cohort yielded an incremental increase in the HR for TTF and overall survival (OS) that reached statistical significance.
6 d9 j9 C- `3 w" aConclusions: In patients with mRCC, early TOI yielded a numerical increase in ORR, TTF and OS, with the TTF difference reaching significance in multivariate analysis. Prospective randomized studies are warranted to examine the impact of chronomodulation on outcomes with ICIs in mRCC.”
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2 L9 N. ]2 [. oICB免疫疗效受昼夜节律调控的现象，一种可能的理论解释是TAM是受昼夜节律调控的，TAM上的pd-1的表达在不同时间是不同的；所以ICB疗效也受昼夜节律调控。具体可以参考下面两篇论文：

" S6 L, g. n6 z! E+ O, }1、《Do macrophages follow the beat of circadian rhythm in TIME (Tumor Immune Microenvironment)?》
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2、《Diurnal Expression of PD-1 on Tumor-Associated Macrophages Underlies the Dosing Time-Dependent Antitumor Effects of the PD-1/PD-L1 Inhibitor BMS-1 in B16/BL6 Melanoma-Bearing Mice》
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