ASH20：不止CAR-T
原文来自中国人民的老朋友：EP的雅各布同志
1 CML
1.1 Asciminib：对比Bosutinib治疗先前≥2种TKi的CML
https://ash.confex.com/ash/2020/webprogram/Paper143816.html
asciminib属于BCR-ABL1的豆蔻酰位点相结合的别构抑制剂，可将BCR-ABL1锁定在非活性构象。asciminib同时靶向作用于野生型BCR-ABL1以及包括T315I在内的突变体。
其实患者基线也不是绝对平衡，比如Asciminib组先前接受过2L治疗的比例就高一些，另外人种上
主要终点MMR 25.5% vs 13.2%
2 AML
2.1 GTB-3550：no responses
https://ash.confex.com/ash/2020/webprogram/Paper136398.html
首先是这家的TRIKE平台，其实就是把分别靶向NK表面的CD16和肿瘤细胞表面抗原的两个scFv用IL-15连接起来，在靶向NK细胞的基础上加入IL-15只在驱动ADCC活性增强杀伤肿瘤的能力及NK细胞的增殖与持久性，另外这里主要激活NK细胞也可以避免因为T细胞过度激活引起的CRS
GTB-3350上靶向的肿瘤抗原是在髓系肿瘤细胞上高表达的CD33，所以入组的是CD33*恶性肿瘤患者，主要是初次诱导化疗或首次诱导化疗后复发的AML，及2轮治疗后进展的高危MDS患者
在Ph1阶段，共6个队列的患者分别接受5-200 mcg/kg/day的剂量，连续给药3周：其中前96小时持续给药然后间隔72小时
一共入了4例患者，5和10 mcg/kg/day各2例，其中3人完成治疗，2例SD，1例携带FLT-3 ITD突变很明显的PD，第一例5mcg/kg/day的厇在第一个疗程后就获得SD，但是因为需要血小板输注随后进行了第2个疗程。这4个完整的疗程都是按照预定计划进行并没有被打断，之前文献报道过rhIL-15 持续输注的MTD是 2 mcg/kg/day，伴随着发热、心动过速和一些其他的全身症状，而这里的临床前模型显示IL15居于2个scFv之间时效能有所降低，接受5和10 mcg/kg/day剂量的GBT3350的患者并未报道有临床免疫激活的迹象或是SAE
相关性的研究显示在所有患者体内都检测到NK细胞的活性：治疗早期NK细胞的活化就有提升(CD69+)，NK细胞的增殖能力在day 3开始升高，在day 8达到峰值后一直持续到day 15-22(Ki-67+)，这些与NK细胞的数量呈现出相关性。通过anti-CD 16将IL-15特异性的递送到NK细胞可以更偏向性于增强NK细胞的增殖而显著减少了CD8+ T细胞的影响。
低剂量没有缓解，高剂量再看看。
2.2 Sabatolimab (MBG453)联合HMA治疗AML及HR MDS的更新
https://ash.confex.com/ash/2020/webprogram/Paper136855.html
This is a phase Ib, open-label, multicenter, dose-escalation study of sabatolimab + HMA (decitabine [Dec] or azacitidine [Aza]) in patients (pts) with AML or HR-MDS (NCT03066648). Pts were adults with newly diagnosed (ND) or relapsed/refractory (R/R; ≥1 prior therapy) AML or IPSS-R high- or very high-risk MDS; pts with chronic myelomonocytic leukemia (CMML) were also eligible. Pts were HMA naive and ineligible for intensive chemotherapy.
这个主要是想在HIC不可耐受的像AML目前治疗范式下做一些探索
选择anti-Tim3单抗主要是报道白血病干细胞及母细胞上高表达Tim3，而在正常造血干细胞上很少，所以可能是治疗AML和MDS的有效靶点。
先看AML
Among 34 evaluable pts with ND AML, overall response rate (ORR) was 41.2%: 8 CR, 3 CRi, 3 PR. Median (range) time to response (TTR) was 2.1 (1.8-13.1) mo and estimated 6-mo duration of response (DOR) rate was 85.1% (95% CI: 68-100%). Estimated 12-mo progression-free survival (PFS) rate was 44% (95% CI: 28-69.3%).
只有阿扎胞苷被EMA正式获批骨髓原始细胞20-30%的1L AML，其余场景主要还是off label，参照VIALE-A中阿扎胞苷组CR 17% CR+CRi 28% OS 9.6mo；而地西他滨单药ORR 28% OS 7.7mo，样本扩大可能就掉了。。。
然后MDS，历史数据ORR 15-30%
Among 35 evaluable pts with HR-MDS, ORR was 62.9%: 8 CR, 8 mCR (5 with hematologic improvement [HI]), 6 SD with HI. Median (range) TTR was 2.0 (1.7-9.6) mo and estimated 6-mo DOR rate for CR/mCR/PR was 90% (95% CI: 73.2-100%). Encouraging response rates were achieved in both pts with high-risk MDS (ORR 50% [11/22]) and very high-risk MDS (ORR 84.6% [11/13]). Of pts with HR-MDS, 8 (5 high-risk, 3 very high-risk) proceeded to transplant. Estimated 12-mo PFS rate was 58.1% (95% CI: 39.9-84.6%).
3 淋巴瘤
3.1 REGN1979
https://ash.confex.com/ash/2020/webprogram/Paper136659.html
纵向和去年比较下≥80mg的数据（今年 vs 去年）
FL ORR/CR 94%/69% vs 100%/70%
RR DLBCL 未接受过CAR-T治疗 ORR/CR 60%/60% vs 71%/71%
RR DLBCL 接受过CAR-T治疗ORR/CR 24%/10% vs 50%/25%
下面是罗氏的2个CD20XCD3双抗
3.2 Mosunetuzumab in DLBCL
https://ash.confex.com/ash/2020/webprogram/Paper136255.html
Among all treated pts, the overall response rate was 58% (11/19) and CR rate was 42% (8/19). At Mosun dose 13.5mg, 3/8 pts (38%) achieved a CR, 2 (25%) had a PR and 3 (38%) had PD at the PRA.
At Mosun dose 30mg, response was available at IRA: 5/11 pts (45.5%) achieved a CR, 1 (9%) had a PR and 5 (45.5%) had PD. Of the 8 pts with PD (from both dosing cohorts), 5 have received salvage therapy post progression.
3.3 Glofitamab/CD20-TCB in RR NHL
https://ash.confex.com/ash/2020/webprogram/Paper136044.html
After a median follow-up of 2.8 months, across all efficacy-evaluable pts (n=32) the overall response rate (ORR) and complete metabolic response (CMR) rate was 62.5% and 40.6%, respectively.
For pts with aNHL (n=24), the ORR was 50.0% with CMR rates of 29.2%. As of the data cut-off date, 17 pts with aNHL (70.8%) had reached the first response assessment only (C3) and remain on treatment; four pts (16.7%) had reached the second response assessment (C6).
For pts with iNHL (n=8), the ORR was 100.0% with 75.0% of pts achieving CMR.
3.4 Trph-222：CD22 ADC
https://ash.confex.com/ash/2020/webprogram/Paper142859.html
从0.6mpk爬到10mpk，在4.2和10mpk各报道1例DLT，也有近半数经历了眼部不良事件，没有检测到脱落的药物，也没有检测到ADA
所有的剂量下给药后外周B细胞下降率50-75%并实现100%的CD22占有率，22例患者中5例CR 1例PR
3.5 MEDI-570 ：ICOS单抗
https://ash.confex.com/ash/2020/webprogram/Paper136465.html
4 MM
4.1 MEDI2228：BCMA ADC
https://ash.confex.com/ash/2020/webprogram/Paper136375.html
4.2 REGN5458：BCMA x CD3
https://ash.confex.com/ash/2020/webprogram/Paper139192.html
4.3 TNB-383B: BCMA x CD3
https://ash.confex.com/ash/2020/webprogram/Paper139893.html
4.4 Talquetamab：GPRC5D x CD3
https://ash.confex.com/ash/2020/webprogram/Paper133873.html
Overall response rate (ORR) for IV doses of 20 – 180 µg/kg was 78% (14/18; 2 pending confirmation); 6/6 responded at the 60 µg/kg IV dose. ORR for SC doses of 135 – 405 µg/kg was 67% (8/12); 3/4 responded at the 405 µg/kg SC dose. Responses were noted starting at 1.0 µg/kg, were rapid at a median of 1 month (0.2 – 3), and durable with median not reached in 36/46 (4 pts with response 15+ months; longest at 23+ months). Data at higher doses are immature, and results will be updated at the meeting.
GPRC5D is a novel target for MM and in the first clinical report of this first-in-class agent, encouraging clinical activity with manageable safety was observed with talquetamab in heavily pretreated pts with RRMM. A MTD has not been defined and dose escalation continues, with the study nearing a RP2D. The encouraging clinical activity supports monotherapy development and combination approaches.
4.5 BFCR4350A：FcRH5 x CD3
https://ash.confex.com/ash/2020/webprogram/Paper136985.html