给免疫治疗“增效”但不“减毒”的药物（五）--Eliglustat、Ceralasertib

第一部分 Eliglustat
/ |  m9 ~- L3 _, l
. \& s) Y- E' R& v
7 _0 |9 t) Z) I" u0 M1、Glycosphingolipids (GSLs) 在癌细胞上大量的表达。抑制GSLs的合成，能增加主要组织相容性复合体(MHC)和肿瘤抗原肽的暴露，增强CD8+T细胞的抗肿瘤反应，对ICB免疫治疗有增敏增效作用。
' ~5 `1 B- z5 ]+ s$ Z2 Q
( U: ?8 S9 `9 [% h' O1 K' K1 A. ^Glucosylceramide(GlcCer), 由 uridine diphosphate-glucose ceramide glycosyltransferase (UGCG)合成, 是所有GSLs的前体。抑制UGCG可以减少GlcCer从而减少GSLs。
' d$ ^' p. i3 F: Z0 f4 O6 H6 R8 e7 ~

' i7 l8 k* B7 v7 i' S2、UGCG抑制剂目前上市的有Eliglustat，是治疗一种罕见的代谢病--戈谢病的药物。


3、《Inhibition of glycosphingolipid synthesis with eliglustat in combination with immune checkpoint inhibitors in advanced cancers: preclinical evidence and phase I clinical trial》
' T9 K& O9 p# l8 j/ }& z$ ]# \
这篇论文讲了Eliglustat 联合ICB的一个前瞻性的临床试验，试验结果证实了Eliglustat对ICB的增敏增效作用。

9 r2 c: g2 ?7 v) L: q9 z+ }" A* C
- t& H& J6 O* J+ U（1）入组的31名患者，有23名患者之前接受过系统性的ICB免疫治疗但没有疗效；另外8名患者是pMMR/MSS 型肠癌患者，pMMR/MSS 型肠癌单用ICB是基本上不可能获益的。
2 c, ?) O9 b" U2 B( `4 j
; B' G0 K9 n$ X7 bTwenty-three patients had received systemic anti-PD-1/PD-L1 therapy prior to enrolment and did not achieve disease remission

, J2 p% J* N6 q/ e* Ythe remaining eight patients with pMMR/MSS colorectal cancer were considered hypo-responsive to PD-1 antibodies

（2）试验结果：ORR 22.6%，DCR 71%。8名pMMR/MSS 型肠癌患者，1人CR，2人PR。
. d4 c4 r! P# i2 Z; J
$ I9 F! Q% Z6 [* R$ tThe objective response rate was 22.6% and the disease control rate reached 71%.

Of the 8 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer, one achieved complete response and two each had partial response and stable disease.

( E# _, ]" q5 K( v（3）毒副作用：31名患者中只有1人出现了3级副作用，没有4级及以上副作用。副作用不大。
/ p  E) c6 I" t& W. n" ^
All prespecified endpoints were met. Among the 31 enrolled patients, only 1 patient experienced a grade 3 adverse event (AE), and no grade 4 AEs were observed.


4、入组患者要么是之前用过ICB没什么用的，要么是pMMR/MSS 型肠癌患者，能有这个疗效非常不容易，说明Eliglustat对ICB的增敏增效作用比较强。

+ r) |& O: K. G6 D4 z# b0 l
2 w3 A8 r6 R; t! `5、在这个临床试验里，Eliglustat 的剂量一开始是用的每天84毫克；后来看到耐受性良好后，后面入组的患者就用的每天168毫克的剂量。
" G( N$ X- X$ c8 H1 r1 n
We initially used a conservative daily dose of 84 mg of eliglustat, taking into account the possibility that the combination could trigger a cytokine storm in patients. After treating 18 patients, no grade 3 or higher toxicity or cytokine storm was observed, so we then increased the oral dose of eliglustat to 168 mg in the remaining 13 patients. During the trial, patients reported mild adverse events (AEs) that were well tolerated.
0 s4 ^0 N0 G2 c6 v  s7 l0 ]% l
; X( A: r4 e, X
+ |" S3 W+ I' i5 X, T4 C6、依利格鲁司(Eliglustat)常见副作用有：头晕；恶心和呕吐；腹泻；肌肉疼痛；头痛；疲劳；皮疹、瘙痒或其他皮肤反应；肝酶升高；嗓子痛、胃灼热感、腹部不适等。

9 f9 I" K! p" T# W

& k% f  x, I. {* l4 P) ^
7 h8 X/ ]& k) n
8 W3 v! c* u# R( l第二部分 Ceralasertib
; [! }8 m  G9 B& [2 N

6 ~+ I! E+ ]* T$ A: O1、Ceralasertib (AZD6738) 是一种口服具有活性的，选择性 ATR 激酶抑制剂，IC50 为 1 nM。CAS号：1352226-88-0。分子量：412.51。

+ g7 m6 b. m  Q0 g1 UCeralasertib目前还没有上市，但是买得到原料药。

2、《Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced/metastatic melanoma who have failed prior anti-PD-1 therapy》这篇论文介绍了一个Ceralasertib联合ICB治疗晚期转移性黑色素瘤的前瞻性临床试验。
7 X+ [+ P# v5 f+ ~9 p
: \1 M) i# E, M$ N( T6 R（1）入组的30名患者全都是之前已经用过pd-1i治疗失败的患者，这是这个临床试验最大的特点。This phase II trial evaluated ceralasertib plus durvalumab for the treatment of patients with metastatic melanoma who had failed anti-programmed cell death protein 1 therapy.

（2）试验结果：ORR 31.0%，DCR 63.3%。PFS 7.1个月，OS 14.2个月。Among the 30 patients, we observed an overall response rate of 31.0% and a disease control rate of 63.3%. Responses were evident across patients with acral, mucosal, and cutaneous melanoma. The median duration of response was 8.8 months (range, 3.8-11.7 months). The median progression-free survival was 7.1 months (95% confidence interval, 3.6-10.6 months), and the median overall survival was 14.2 months (95% confidence interval, 9.3-19.1 months).

（3）毒副作用：常见副作用主要是贫血、血小板减少、中性粒细胞减少症、恶心、厌食等，有53.3%的患者出现了3级副作用。
; u3 p4 r: Z/ N# T8 |
Among the 30 patients who received at least one dose of both ceralasertib and durvalumab, treatment-emergent adverse events (Aes) of any grade occurred in 29 patients (96.7%) (Table 2). More than half of the patients experi enced anemia (76.7%), anorexia (66.7%), thrombocytopenia (63.3%), and nausea (56.7%). Sixteen patients (53.3%) re ported treatment-emergent Aes with grade 3, the most common of which were anemia (33.3%), thrombocytopenia (16.7%), and neutropenia (16.7%). These hematologic Aes are expected Aes of ceralasertib and durvalumab. All Aes of grade 3 improved following interruptions to drug admin istration and supportive care, including intermittent trans fusions, if needed.

; X5 X+ {9 @1 |. F( r7 u3 |有一位患者死于中性粒细胞减少症。

There was a treatment-related death (ID19). The patient developed febrile neutropenia after 30 days from the initiation of the study treatment (ceralasertib 240 mg b.i.d., durvalumab 1500 mg). No other medication possibly related to the neutropenia was administered. Therefore, we considered the event was causally related to the study treatment. Despite best supportive care, including the administration of broad-spectrum antibiotics, the patient eventually died.

0 s# ~/ Q" s3 ~, B& `安全问题还是要引起注意。除了减少Ceralasertib 的剂量外，我觉得更好的治疗策略还是应该同时联用给 ICB 减毒增效的参芪扶正注射液、人参多糖注射液、复方苦参注射液之类的药物，减少血液毒性。（见《给免疫治疗“减毒增效”的辅助药物（十六）：中药、中成药 3》等文章）

' `* [4 v2 k6 q$ e, A
! D/ {5 Z8 {3 {（4）Ceralasertib的剂量：28天一个周期，每个周期的15-28天，每天两次，每次240毫克Ceralasertib。
3 T4 v$ Y* _: p) Q$ y3 k* J
8 ?; V/ @0 {0 ^1 U( T6 bfol lowed by 240 mg of ceralasertib twice daily on days 15-28.

如果出现了副作用可以减Ceralasertib的剂量，减成每天两次每次160毫克。

5 U* Z- M; _  S% V. Y# M% Y/ Yfrom 240 mg b.i.d. to 160 mg b.i.d