给免疫治疗“减毒增效”的辅助药物（六）--维生素D和维生素B5
一、维生素D1、《Vitamin D supplementation increases objective response rate and prolongs progression-free time in patients with advanced melanoma undergoing anti–PD-1 therapy》
这篇论文讲了波兰的一个前瞻性的对照试验，icb免疫治疗补充或者不补充维生素D。
试验组以血清维生素D 30ng/ml为标准来分组，将200名黑色素瘤患者分为两组：
维生素D缺乏组包括两类患者，基线检测血清维生素D低于30ng/ml且一直未补充维生素D的患者 + 基线检测血清维生素D低于30ng/ml且补充了维生素D但一直未能超过的患者。维生素D缺乏组的患者血清维生素D在icb治疗期间一直都是低于30ng/ml的。
维生素D正常组包括两类患者，血清维生素D一直高于30ng/ml的患者 + 基线检测血清维生素D虽然低于30ng/ml但补充了维生素D后超过的患者。
维生素D正常组的患者血清维生素D在icb治疗期间一直都是高于30ng/ml的。
试验组补充维生素D的维持剂量是每天2000 IU；如果要大量补充是每天4000-6000IU。
联合icb治疗后：
维生素d正常组的 objective responses 客观反应率是 56.0% (79/141)；维生素d缺乏组的客观反应率是 36.2% (21/58)；p=0.0111，差异有统计学意义。
维生素d正常组的 pfs 是11.25月 (95% CI, 6.25–20.25)；维生素d缺乏组的pfs 是 5.75月 (95% CI, 3.0–11.50)；p=0.0378，差异有统计学意义。
2、《Vitamin D Status Is Associated With Immune Checkpoint Inhibitor Efficacy and Immune-related Adverse Event Severity in Lung Cancer Patients: A Prospective Cohort Study》
Vitamin D (VitD) is potentially immunomodulatory, so here we aimed to explore the relationships between serum VitD levels, immune checkpoint inhibitor (ICI) efficacy, and immune-related adverse events (irAEs). Serum 25-hydroxyvitamin D levels were quantified before and after ICI treatment in prospectively enrolled patients with advanced lung cancers. Of 77 enrolled patients, 29 developed 42 irAEs. Baseline 25(OH)D levels of partial response (PRs) patients were significantly higher than non-PR patients (19.39±7.16 vs. 16.28±5.99 ng/mL, P =0.04). The area under the curve of 25(OH)D >15.73 ng/mL to identify PR was 0.63 (95% CI, 0.51-0.76, P =0.047), and baseline 25(OH)D levels >15.73 ng/mL (odds ratio: 2.93, 95% CI, 1.10-7.79, P =0.03) and prior targeted therapy (odds ratio: 0.30, 95% CI, 0.10-0.92, P =0.04) were independent predictors of PR as best efficacy by multivariable logistic regression. With respect to irAEs, baseline 25(OH)D levels were higher in grade 1 irAE patients than in grade 2/3/4 irAE patients (20.07±8.64 vs. 15.22±2.30 ng/mL, P =0.02). However, the area under the curve was only 0.56 (95% CI, 0.42-0.70, P =0.39) for a baseline 25(OH)D of 20.99 ng/mL for predicting irAE occurrence. There was a direct monotonic relationship and U-shaped relationship between baseline 25(OH)D levels and ICI efficacy and irAE occurrence, respectively. Overall survival was significantly different between VitD sufficient, insufficient, and deficient patients (log-rank P =0.01), which remained after adjustment in Cox proportional hazards regression models. Baseline 25(OH)D levels seem to be associated with ICI efficacy and prognosis, it might be helpful to assess the baseline VitD status, and supplementation with VitD might bring some benefit to enhance ICI efficacy and reduce moderate-severe irAEs.
二、维生素B5
《Coenzyme A fuels T cell anti-tumor immunity》
Given these findings, we tested whether pantothenate could be associated with responses to anti-PD1 therapy in humans. Using mass spectrometry, we detected over 100 different metabolites in plasma samples from 42 patients with Stage III or Stage IV melanoma prior to these patients receiving anti-PD1 antibody therapy (21 responders and 21 non-responders). Pantothenic acid was the most enriched metabolite in patients who demonstrated response to anti-PD1 therapy (Figure 6D). A waterfall plot analysis revealed that patients with the top 1/3 of pantothenic acid plasma levels were mostly responders, whereas the bottom 1/3 of patients contained equal numbers of both responders and non-responders (Figure 6E). This is suggestive of a threshold effect in which a certain threshold level of plasma pantothenic acid must be reached to derive clinical benefit. In support of this, we found that patients with the highest plasma pantothenic acid levels demonstrated a significantly longer time to next treatment (TTNT) compared to patients with lower levels (Figure 6F). Additionally, we found that melanoma patients responding to anti-PD1 therapy upregulated many genes associated with the Tc22 lineage (Figures 3E and 3F), including IL-22 (Figure 6G), as determined by re-analyzing a previously published dataset of gene expression profiles of on-treatment tumor biopsies from a different cohort of patients (Chen et al., 2016). Together, these findings suggest an important role for pantothenate metabolism in influencing the response to PD-1 checkpoint blockade.
看图的E部分
血清泛酸达到 1 X 10⁵ 阈值的11位患者，9个对icb治疗有应答，应答率81.81%；
血清泛酸低于 5 X 10⁴ 阈值的17位患者，7位对icb治疗有应答，应答率 41.17%。
差异明显。
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