ESMO大咖访谈|齐长松教授:针对GCC的CAR-T疗法IM96在晚期结直肠癌中表现出显著的抗肿瘤活性

作者:肿瘤瞭望   日期:2023/11/13 12:47:34  浏览量:2578

肿瘤瞭望版权所有,谢绝任何形式转载,侵犯版权者必予法律追究。

北京大学肿瘤医院齐长松教授在本次会议上作重要口头报告(摘要号:1018O)。在《肿瘤瞭望》的现场访谈中,齐长松教授分享了自己汇报的研究,以及对今年ESMO会议发布的结直肠癌研究的见解。本期整理了相关内容,以飨读者。

编者按:2023年欧洲肿瘤内科学会(ESMO)年会已于10月20日~24日在西班牙马德里召开,肿瘤瞭望前方报道团队深入一线,直击国际前沿进展,见证中国抗肿瘤事业在国际舞台上开拓前行。北京大学肿瘤医院齐长松教授在本次会议上作重要口头报告(摘要号:1018O)。在《肿瘤瞭望》的现场访谈中,齐长松教授分享了自己汇报的研究,以及对今年ESMO会议发布的结直肠癌研究的见解。本期整理了相关内容,以飨读者。

肿瘤瞭望:您在今年ESMO会场汇报了针对GCC的CAR-T疗法IM96治疗晚期结直肠癌的I期研究,请您谈一谈此项研究的研究背景、主要研究结果,以及您后续的研究计划?
齐长松教授:目前免疫检查点抑制剂为代表的免疫疗法非常火热,但是在某些实体瘤当中的疗效并不显著,尤其是在消化系统肿瘤,获益有限。这种情况下,我们可能需要探索更多的免疫疗法,因此开展了此项针对GCC(guanylyl cyclase C,鸟苷酸环化酶C)的CAR-T疗法IM96治疗晚期结直肠癌的I期研究。
为什么我们选择在结直肠癌做这种探索?首先,结直肠癌属于全球的大瘤种,其发病率和死亡率均排在恶性肿瘤的前五位,因此以结直肠癌为适应症可以为尽可能多的患者带来获益。其次,结直肠癌比较特殊,根据分子分型可分成MSI-H型和MSS型。MSI-H型结直肠癌能从免疫检查点抑制剂中显著获益,但是这部分患者在晚期结直肠癌患者中占比太低,仅5%左右,而其余约95%患者均属于MSS型,难以从免疫检查点抑制剂中获益。我们需要为这类患者找到其他有效疗法,所以探索了针对GCC的细胞免疫治疗。
GCC在80%以上的转移性结直肠癌中高表达,原发灶和转移灶均高表达GCC,并且正常组织较低表达,仅正常肠道黏膜有一定程度表达。因此,GCC是一个比较理想的CAR-T靶点,在此项临床试验中也得到了验证。IM96的安全性非常好,未发生较严重的细胞因子释放综合征(cytokine release syndrome, CRS)和神经毒性。9例患者当中有6例患者出现腹泻,大部分为轻到中度,并且在细胞输注后十天就能很好地恢复。在有效性方面,此项研究是一个剂量递增实验,在前面两个剂量时,一些患者的肿瘤标志物出现了下降,第3例患者出现肿瘤明显退缩。在中高剂量组取得了非常好的疗效,并且疗效与GCC表达成一定的正相关。
后续的研究计划有如下几个方面。首先,我们需要探索更高剂量的有效性和安全性,以及在更高表达GCC的患者中探索IM96的有效性和安全性。其次,因为IM96的不良反应可控,并且与靶向治疗、免疫治疗和化疗等治疗的不良反应谱完全不同,并且理论上PD-1单抗、CTLA4单抗、肿瘤疫苗或溶瘤病毒等疗法联合细胞治疗会产生协同效应,产生1+1>2的效果,所以我们可能会探索IM96和其他疗法的联合治疗。最后,我们还计划探索针对其他靶点的药物。总之,我们希望通过不停地探索能够为消化系统肿瘤患者带来更好的获益。
 
02
肿瘤瞭望:今年ESMO会议公布了多项结直肠癌领域的研究,请您分享一下您对此次会议发布的研究的看法?
齐长松教授:今年ESMO会议公布的结直肠癌研究,涉及围手术期放化疗联合免疫治疗和晚期结直肠癌免疫治疗,这些治疗方法都非常火热,但是归根结底仍然是在结直肠癌当中,探索免疫检查点抑制剂为代表的免疫治疗。这些探索在早期肠癌当中可能有一定的进步空间,但是在晚期肠癌当中目前看来整体疗效进展有限。当然,有些研究给我留下了非常深刻的印象,它们探索了“Biomarker(生物标志物)”、免疫微环境等,这有助于我们理解结直肠癌对治疗的反应机制,以及对相应药物的耐药机制,进而对后续药物的研发或者疗法的改进具有重大帮助。
摘要原文
上下滑动查看更多内容
1018O - Phase I study of GCC CAR-T therapy IM96 in patients with advanced colorectal cancer
Background
The clinical outcomes of metastatic colorectal cancer (mCRC) therapies are limited. Guanylyl cyclase 2C (GCC) is ectopically expressed in mCRC and intestinally-restricted. A GCC-targeted CAR-T (IM96) was developed and phase I study was conducted to evaluate the safety and efficacy (NCT05287165).
Methods
In this open-label, 3+3 dose-escalation study, IM96 was evaluated in GCC-positive mCRC patients (pts) failed to ≥3 lines of therapies. Bridging therapies were allowed. Pts were pre-treated with fludarabine and cyclophosphamide, and received a single infusion of IM96 at the dose of 3×108 (DL1), 6×108 (DL2), 12×108 (DL3), or 20×108 (DL4) CAR-T cells. The primary objectives were safety and toxicity, and the secondary objectives were efficacy and pharmacokinetic profile.
Results
As of December 2022, 9 pts were enrolled and infused with IM96. The median age was 52.6, and 5/9 cases were male. Bridging therapies were used in 8 pts. Neurotoxicity and ≥grade 3 cytokine release syndromes (CRS) were not observed. Grade 1-2 CRS occurred in 5/9 pts (55.6%) with dramatic increase of interleukin-6. In 4/9 pts (44.4%), grade 1-3 diarrhea and rash were observed. Grade 3 diarrhea occurred in 2/9 pts (22.2%), and grade 2-3 oral mucositis occurred in 3/9 pts (33.3%), only in DL2 and DL3 groups. Dose-limiting toxicity and maximum tolerated dose were not achieved. The disease control rate (DCR) was 66.7%, and the objective response rate (ORR) was 11.1%. After CAR-T infusion, 5/9 (55.6%) patients showed a significant decrease in CEA level which was aberrantly high in all pts at baseline. CAR-T proliferated in all pts and reached peak at 7-10 days after infusion. Two pts showed persisting tumor reduction and declination of CEA level within 3 months, coinciding with CAR-T expansion to 108/L. The response in pts with moderate-to-strong GCC expression in ≥30% of tumor cells was 100% DCR, and with this prerequisite, tumor reduction was observed in 100% pts when the IM96 dose was ≥6×108.
Conclusions
IM96 was well tolerated and showed encouraging efficacy. The clinical response is correlated with tumor GCC expression, infusion dose, and CAR-T expansion level. This study is ongoing, and dose extensive investigation will also be performed.
Clinical trial identification
NCT05287165.

 

版面编辑:高金转  责任编辑:卢当鹏

本内容仅供医学专业人士参考


ESMO 2023,齐长松教授,CAR-T疗法,结直肠癌

分享到: 更多