大会期间，《肿瘤瞭望消化时讯》特邀英国伦敦大学医院Kai-Keen Shiu教授，围绕结直肠癌免疫治疗耐药问题、当前在研的联合治疗策略、生物标志物的应用价值，以及制约疗效突破的临床试验设计瓶颈展开深度分享。Kai-Keen Shiu教授同时结合全球研究经验，对中国开展高质量创新临床研究给出独到见解。现将访谈精粹整理如下。
Kai-Keen Shiu 教授
长期以来我们已知，绝大多数肠癌患者为微卫星稳定（MSS）、错配修复功能完整（pMMR）肿瘤。晚期患者中，这类人群占比超90%；而在早期人群中，占比也达70%~80%以上。
KEYNOTE-177、CheckMate-8HW、NICHE2等多项研究证实，微卫星高度不稳定（MSI-H）肿瘤患者可从免疫治疗中获得突破性疗效。免疫治疗能够激活强效免疫应答，调动免疫系统识别并清除癌细胞，原理类似机体清除病毒或细菌。但MSS肿瘤无法产生这类免疫应答。这严格来说并不属于传统意义上的耐药，而是肿瘤本身的生物学特征导致免疫治疗难以起效。本质上，这类肿瘤可产生新生抗原（即外源样抗原）的突变数量极少。
因此PD-1或CTLA-4抑制剂无法诱发预期的抗肿瘤免疫应答，目前耐药相关机制尚未完全阐明，免疫治疗的确切作用机制也有待进一步解析。尽管如此，利用宿主自身免疫系统清除肿瘤仍是极具前景的治疗策略。我们预估至少1/4的MSS患者可对免疫治疗产生应答，我们的核心任务就是筛选出这部分亚组人群。对于其余患者，则需要调整治疗药物或重塑肿瘤微环境。相关策略包括联合其他免疫检查点抑制剂、肿瘤疫苗、不同化疗方案、放疗以及靶向治疗。
Q1：Could you briefly elaborate on immunotherapy resistance in colorectal cancer, and what are the major challenges in managing patients with treatment-resistant tumours?
Prof. Kai-Keen Shiu：
What we have long known about bowel cancers is that most patients have microsatellite-stable or MMR proficient cancer. In the advanced setting, this accounts for over 90% of patients, and in early-stage disease, over 70~80% of patients.
In contrast to the transformative treatment outcomes observed in MSI-High cancers from KEYNOTE-177, CheckMate-8HW, NICHE2 and other studies, immunotherapy can elicit a robust immune response whereby the immune system targets and eliminates cancer cells, similar to how it clears viruses or bacteria. This response is not seen in microsatellite-stable cancers. It is not truly resistance per se; rather, the underlying biology renders immunotherapy ineffective. Essentially, these tumours harbour few mutations capable of generating so-called neoantigens, or foreign antigens.As such, PD-1 or CTLA-4 inhibitors fail to induce the expected anti-tumour immune response. The mechanisms of resistance remain incompletely understood, and we still lack full clarity on the precise mode of action of immunotherapy. Nonetheless, harnessing the host immune system to eradicate cancer represents a highly promising therapeutic strategy. We estimate that at least one-quarter of patients with microsatellite-stable disease may respond, and our task is to identify this patient subgroup. For the remainder, we need to modify treatment agents or remodel the tumour microenvironment. Strategies include combinations with additional checkpoint inhibitors, vaccines, various chemotherapy regimens, radiotherapy and targeted therapies.
Kai-Keen Shiu 教授
我的报告主要围绕MSS肿瘤的免疫治疗开展。简单来说，其中一种策略是采用新一代免疫检查点抑制剂——Fc改造型CTLA-4抑制剂，将“冷肿瘤”转化为“热肿瘤”，以此克服耐药。我们同时也在探索直肠癌放疗联合方案，以及肿瘤疫苗。
还有一个我未深入展开的关键话题：即便是错配修复缺陷（dMMR）肿瘤，尽管目前已有有效的免疫治疗方案，即便采用纳武利尤单抗联合伊匹木单抗双免方案，仍有约10%~15%患者存在原发免疫耐药，或是后续发生获得性耐药。相关潜在机制尚未完全阐明，但已有多项新兴治疗手段正在研发，例如利用DNA合成致死效应的Werner解旋酶抑制剂。我们也在评估新一代CTLA-4抑制剂与肿瘤疫苗的联合方案。
虽然免疫治疗彻底改变了MSI-H肿瘤患者的诊疗格局，但耐药问题依旧可能发生。我在报告中重点探讨的另一内容，是如何在疾病进展前，借助生物标志物预判耐药风险。我们还可以采用动态实时循环肿瘤DNA（ctDNA）检测，或是其他基线生物标志物，为MSS或MSI-H患者预判后续最优治疗方案。
Q2：For colorectal cancer patients who get limited benefit from immunotherapy and develop resistance, what strategies are currently being explored? What do you believe are the key directions to overcome immunotherapy resistance?
Prof. Kai-Keen Shiu：
My talk was mainly around immunotherapy for MSS tumors. Briefly, one approach is using new-generation checkpoint inhibitors, Fc-engineered CTLA-4, to turn cold tumors hot and overcome that resistance. We are also exploring radiotherapy in rectal cancers, and potentially vaccines.
The other important question which I did not elaborate on is that even for MMR-deficient tumors, although we now have effective immunotherapy options, even with doublet nivolumab-ipilimumab, around 10 to 15% of patients exhibit primary immunotherapy resistance or develop acquired resistance. The underlying mechanisms remain incompletely understood, yet we have other emerging therapeutic options for example Werner helicase inhibitors that exploit DNA synthetic lethality. We are also evaluating using next generation CTLA-4 inhibitors combinations with vaccines too.Although immunotherapy has transformed patient care for MSI-H cancers, resistance may still emerge. A key point I also discussed is how we may identify biomarkers to predict this resistance before disease progression occurs. We can also use dynamic ‘real time’ ctDNA testing or other baseline biomarkers to help predict what the optimal subsequent treatment will be for these patients whether they have MSS or MSI-H cancers.
Kai-Keen Shiu 教授
传统新药研发模式，是先在多线化疗失败的晚期患者中开展临床试验。化疗起效迅速，但免疫治疗，尤其针对MSS肿瘤时，往往需要更长时间才能显现疗效。一旦肿瘤广泛转移，累及肝、骨、胸膜、腹膜等多个部位，患者留给治疗起效的时间十分有限，全身状况会快速恶化。因此我们认为，应当在更早疾病阶段开展药物试验：比如仅接受过一线化疗后的患者，或是在术前新辅助治疗阶段开展联合方案研究，此阶段肿瘤的免疫敏感性更高。
另一项局限在于治疗过程中动态检测不足。我们需要在更早疾病阶段开展更多早期临床试验，在治疗前、治疗中、治疗后连续采集活检标本评估药物活性。这些结果能够指导患者继续或终止治疗，对试验设计也具备直接参考价值。
中国拥有大量可入组临床试验的患者资源。如果我们能够精巧设计试验，利用生物标志物指导患者分层给药，将是最优路径。所以当前的治疗瓶颈并非缺少新药或是受试患者，而是缺少构思严谨、设计周密、以生物学机制为导向的临床试验。
Q3：Although dMMR/MSI-H patients derive clear benefits, the majority pMMR/MSS colorectal cancers remain "cold tumors" facing severe resistance challenges. From an international perspective, what do you see as the core bottleneck limiting efficacy in these immuno-resistant patients? Among current combination strategies or emerging targets, which explorations hold the most promise to break this deadlock?
Prof. Kai-Keen Shiu：
Traditionally, when we test new drugs, we first evaluate them in the very advanced disease setting, in patients who have received multiple prior lines of chemotherapy.
We know chemotherapy does work rapidly whilst immunotherapy may take more time to exert its effect especially if MSS. If a tumour has spread to multiple sites including the liver and bone, pleural and peritoneal disease, the patient does not have much time to respond to any treatments, and their clinical condition can deteriorate very quickly. Therefore, we believe we should test these drugs in earlier disease settings, meaning initiating treatment after patients have received only one line of chemotherapy or test combinations in the preoperative/neoadjuvant settings where the tumours are more immune-senstive.Another limitation is that we do not perform sufficient dynamic testing during treatment. We need to conduct more early-phase trials in earlier-stage disease, with serial biopsies collected before, during and after treatment to assess drug activity. This informs treatment continuation or discontinuation for patients and is directly relevant to trial design.China has a large patient pool eligible for clinical trial enrolment. If we design trials smartly and use biomarkers to guide treatment allocation, this will represent the optimal approach. Therefore it is not a lack of novel drugs or patients; the bottleneck lies in not having enough well-conceived, thoughtfully designed, biologically driven clinical trials.
专家简介
- 专业方向
- 胃肠道恶性肿瘤和未知原发肿瘤的免疫疗法
- 主要参与研究：
JavelinGastric100，GS-US-296-2013，POLEM，KEYNOTE 177、 KEYNOTE 811、 KEYNOTE 859等大型临床研究
医院任职&学会资格
NCRI CUP Workstream 主席
NCRI大肠癌和辅助疾病亚组成员
伦敦大学癌症研究所/ Francis Crick研究所的胃肠道肿瘤学和CUP亚组成员
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