给免疫治疗“增效”但不“减毒”的辅助药物（一）：锰

我现在逐步转变了观念，觉得在大量应用有消炎作用的“减毒增效”药的前提下，适当用一些“增效”但不“减毒”的辅助药物，也不是不可以。但对无法及时止损，结果不可逆的放疗之类的增敏增效手段，始终保持警惕。


锰
$ n) p8 P3 |+ Z- d$ O$ \' ]3 S8 @
《Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy》

“Based on the aforementioned data, we conducted a first-in human, open-label, dose-escalation phase 1 clinical trial to assess the safety and preliminary efficacy of Mn2+ priming anti-PD-1 antibody plus chemotherapy (ClinicalTrials.gov, NCT03991559). From November 25, 2018 to May 15, 2019, twenty-two patients with advanced metastatic solid tumors were enrolled, and received at least two doses of the combined therapy (Fig. (Fig.7a–c; Supplementary7a–c; Supplementary information, Tables S2, S4, S5). MnCl2 solution was administered intranasally or by inhalation (as described in the Materials and Methods). At data cutoff on April 15, 2020, all patients experienced at least one evaluable post-treatment tumor scan, and showed preliminary favorable clinical efficacy with 45.5% (95% CI, 26.9–65.3) best objective response and 90.9% (95% CI, 72.2–97.5) best disease control rate (Fig. 7b; Supplementary information, Fig. S7a). Consistently, the clinical responses correlated well with the in vitro Mn2+ responses by PBMCs isolated from these cancer patients (Supplementary information, Table S2). Critically, all five patients who failed the previous combined treatment of anti-PD-1 antibody and chemotherapy or radiotherapy showed disease control, including three with partial response (PR) and two with stable disease (SD), suggesting that Mn2+ revived antitumor immunotherapy in these immune unresponsive patients. Remarkably, slough of necrotic tumor mass from chest wall in one breast cancer patient and largely relief of frozen pelvis in six ovarian cancer patients were observed (Fig. 7c). Concentration of blood free Mn was detected by differential-pulse polarographic determination with a normal range between 0.029 μM and 1.2 μM, which is different with inductively coupled plasma-atomic emission spectroscopy (ICP-AES) recommended by ATSDR (Supplementary information, Data S1). Importantly, post-administration blood Mn levels were elevated but remained within the normal range, and it appeared to predict its antitumor effects (Fig. 7d). Stratification by clinical responses demonstrated that a significant increase of Mn concentration was observed in patients who achieved PR and SD with decreased lesions (Cohort 2) but not in patients with PD and SD with enlarged lesions (Cohort 1), and remained elevated for at least 12 weeks (Fig. 7e). Elevated blood Mn promoted the induction of type I IFNs and some pro-inflammatory cytokines, as statistically significantly increased IFNα, IL-6, IL-8 and TNFα were observed in Cohort 2 (Fig. 7e; Supplementary information, Fig. S7b, Cohort 2), consistent with the immunostimulatory effects of Mn2+ in mouse models and human PBMCs.”

“This phase 1 trial documented a manageable safety profile, any-grade treatment-related adverse events (AEs) occurred in 19 (86%) patients and serious treatment-related AEs (grade 3–4) in nine (41%) patients without any treatment-related death (Supplementary information, Table S6). The grade 1–2 AEs were well tolerated and grade 3–4 AEs resolved with supportive cares. Five patients discontinued treatment because of immune-related pneumonitis (n = 2) and chemotherapy-related hematological and gastrointestinal toxicities (n = 3). With a median follow-up of 11.8 months, no Mn overdose-related toxicity and accumulation of Mn in the basal ganglia was observed.57 Importantly, five patients with extensive metastases in abdominal cavity developed acute suspected local or systemic cytokine-release-syndrome (CRS) with apparent induction of serum type I IFNs and some pro-inflammatory cytokines including IL-6 and TNFα (Supplementary information, Fig. S7c, d), accumulated ascites, diarrhea, ileus and hypoxemia resulted from pleural effusion and pulmonary edema (Fig. 7f), but all resolved by the use of anti-TNFα/TNFαR or anti-IL6R antibody alone. Radiographic data of all 22 patients before and after treatment were all exhibited (Supplementary information, Fig. S8). This phase 1 study thus provided preliminary encouraging evidence supporting the safety profile and antitumor effects of Mn2+ in patients with advanced metastatic solid tumors, and now a phase 2 study is ongoing.”
0 j0 U- b; ~: t: a6 E6 `
: W$ Q& b6 y% t  m7 u# [, gDrug: Manganese Chloride
8 K& B' q  s& R8 x# y2 C
8 B1 `: h, S/ F3 v, P/ bAdministered intranasally in Arm 1 (0.05, 0.1 or 0.2 mg/kg/d) and by inhalation in Arm 2 (0.1, 0.2 or 0.4mg/kg/d) once daily in a 3-week cycle

Drug: Anti-PD-1 antibody

Administered intravenously, at 2-4mg/kg on day 3 in a 3-week cycle

. K1 f4 @# }- F- I. {
8 t7 E4 X0 m$ n9 B0 P/ w这个临床试验比较有价值的地方是几位ICB耐药的患者又重新复敏了。
0 X$ G4 E. R* O1 d: }; J$ k! }
- C7 z  S7 C5 U; b但有5名患者疑似出现了CRS，风险还是比较大的。所以一定要跟抗组胺药、己酮可可碱、异丁司特、复方苦参注射液这些消炎药一起用才行。