ASH18 (补清晰图)简单收尾
昨天推送图片不清，今日更新后重新推送
继续昨天的BCMA CAR T，墙外有人把靶向BCMA的CAR-T、双抗、ADC作了比较
https://pbs.twimg.com/media/DtmSqeQWsAYe_UU.jpg
外FDA的报告
2018 saw 32 FDAapprovals in hematology including 12 NMEs & 5 biosimilars. 8 had pediatric indications. 6 were for1st-line indications. We used the Real-Time Oncology Review to approvebrentuximab vedotin 2 wks after receiving the company's completed application.
vantage也评价了他们眼中的best of ASH18
1）BCMA阴性的多发性骨髓瘤中用GPRC5D CAR T可以清除恶性肿瘤细胞，但是还只是mouse model，明年1季度开始phase 1
This protein, G protein-coupled receptor class C group 5 member D in full, is present on plasma cells, but what makes it really interesting is that its expression is independent of BCMA. This means that it could be a target for treating multiple myeloma in patients who have relapsed on anti-BCMA therapy.In a mouse model of multiple myeloma with BCMA knocked out, the anti-GPRC5D CAR cleared malignant cells. A first clinical trial – including patients who progressed after BCMA therapy – begins in the first quarter.
2) NCI的hu19-CD828Z，一切结果源于设计，相比FMC263-28Z除了全人源的scFv——hu19代替了鼠源的FMC63以外，重要的而变化在与用CD8的铰链区和跨膜区替换了CD28的相应区域，在之前的小鼠模型中发现两者消除肿瘤能力相近，但是CD8替换后炎症因子产生降低，另外也表现为低AICD
除了上述差异，病毒也不一样，FMC63-CD28Z是逆转录病毒，而hu19-CD828Z是慢病毒！！！
患者体内的细胞因子分泌和小鼠实验一致，hu19-CD828Z引起分泌的水平更低
比较：临床效果相近，但hu19-CD828Z的神经毒性更低，研究也提出这可能和细胞因子产生降低相关
It has been known for some time that the use of murine binding domains in CAR-T therapy could lead to rejection and low persistence of the cells. Several institutions are therefore developing fully human binders.
But direct comparisons of the two are few and far between – a situation the NCI’s Dr James Kochenderfer remedied at Ash. His comparison of two trials showed similar remission rates in lymphoma patients treated with the NCI’s fully human construct to that seen with a murine CAR: 70% versus 73%.But what set the pulses racing was a staggering reduction in toxicity: only 5% of subjects treated with the human construct experienced serious neurotoxicity, versus the more usual 55% treated with the mouse CAR. The only remaining question is why so many companies and institutions still focus on CARs with murine binders.
3）也就是首日提及的 MSKCC auto/trans co-stimulated CD19 CAR T，下面是前日文字，不再赘述，亮点也是没有3-4级CRS、3-4级神经毒性NTX较少。
加了截短的EGFR，除了共刺激的CD28之外，在膜上表达了4-1BBL：CD28 CAR功能更强，4-1BB更持久——这样除了激活同个T细胞上的4-1BB/4-1BBL通路（auto），还能激活其它T细胞上的4-1BB/4-1BBL通路（trans），临床前的结果显示抗肿瘤效果更加平衡，通过提高CD8+ T/CD4+ T 的比例和降低耗竭来提升T细胞持久性，另外这种改造也诱导T细胞中IRF7/INFβ通路来优化CAR-T介导的肿瘤清除
CRS和神经毒性：
整体上CRS 62%，但是没有观察到严重CRS
整体上NTX 34%，3-4级的6%，但没有观察到4-5级NTX和脑水肿
And the winner is... a next-generation CAR construct with a completely separate co-stimulatory domain, whose concept has been expounded for some years by Sloan Kettering’s Dr Michel Sadelain. This comprises a membrane-bound 4-1BBL (the ligand, as opposed to 4-1BB itself), and is designed to cause additional stimulation of bystander T cells to result in potent tumour killing.Ash saw Dr Jae Park present the first clinical data from this so-called third-generation “armoured CAR”. Remarkably, in just a few months this trial has managed to yield 28 evaluable haematological cancer patients, giving an impressive 82% overall response rate, with 15 complete remissions.But again it was safety that truly amazed, with just three grade 3 neurotoxicities and zero incidence of serious cytokine release – a virtually unheard of finding in this patient population.