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。
01. 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
1018O - Phase I study of GCC CAR-T therapy IM96 in patients with advanced colorectal cancer
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.
