摘要：2024年11月14日至17日，国际细胞与免疫治疗（CTI）大会在中国杭州盛大举行，汇聚了全球细胞治疗和免疫治疗领域的顶尖专家、学者和行业领袖。此次大会不仅是一个学术交流的国际平台，更是一个展示最新科研成果、推动领域发展的重要窗口。会议期间，《肿瘤瞭望-血液时

2024年11月14日至17日，国际细胞与免疫治疗（CTI）大会在中国杭州盛大举行，汇聚了全球细胞治疗和免疫治疗领域的顶尖专家、学者和行业领袖。此次大会不仅是一个学术交流的国际平台，更是一个展示最新科研成果、推动领域发展的重要窗口。会议期间，《肿瘤瞭望-血液时讯》特别邀请到美国埃默里大学血液和骨髓移植中心主任Edmund K Waller教授，为我们深入剖析了细胞与免疫治疗在癌症治疗中的重要地位，以及新型免疫检查点通路VIP的发现及其拮抗剂的研发进展。现整理成文，以飨读者。

Q1

您在癌症免疫疗法领域有着深厚的造诣，特别是针对新型免疫检查点通路的研究。能否请您简要介绍一下这一领域的研究现状，以及您为何选择这一方向作为您的研究重点？

Edmund K Waller教授：非常荣幸能够来到杭州，参与此次国际细胞与免疫治疗大会。我作为一位受过专业训练的肿瘤学家，经常接诊那些在经历标准化疗后病情仍旧持续恶化的癌症患者。细胞治疗与免疫治疗作为癌症治疗的第四大支柱，其重要性日益凸显。回顾癌症治疗的历史进程，我们首先采用的是手术治疗，随后是放射治疗，紧接着是化疗。而现在，免疫治疗为那些对早期治疗手段无应答的癌症患者点亮了新的希望之光。免疫治疗凭借其独特的作用机制，能够有效克服癌细胞对化疗药物的耐药性，精准追踪并清除体内任何部位的癌细胞。因此，我深信免疫治疗为患者带来了前所未有的希望，同时也展现出巨大的治疗潜力。

Oncology Frontier-Hematology Frontier：Professor,you have extensive expertise in the field of cancer immunotherapy, particularly in the research of novel immune checkpoint pathways. Could you briefly introduce the current research landscape in this area and why you chose this direction as your research focus?

Dr.Edmund K Waller: It's my pleasure to be here in Hangzhou and at the cellular therapy and immunotherapy conference. I'm trained as an oncologist and I treat patients with cancer often whose disease has progressed after standard chemotherapy. Cellular therapy and immunotherapy represent the fourth leg of therapy in cancer. First, there was surgery, then there was radiation. Then chemotherapy. And finally, immunotherapy is offering new hope for patients whose cancer hasn't responded to one of the earlier treatments. Immunotherapy can overcome resistance of cancer cells to chemotherapeutic agents and can seek out and destroy cancer cells wherever they are in the body. So I feel it offers great hope for patients and great therapeutic potential.

Q2

新型免疫检查点通路与已知的免疫检查点（如CTLA-4、PD-1等）相比，有哪些独特之处？这些独特之处是否意味着新型免疫检查点通路在治疗上具有更大的潜力？对于癌症患者而言，这意味着什么？

Edmund K Waller教授：我们已成功鉴定出一种新型免疫检查点通路，该通路由小型神经肽VIP所介导。VIP在调节机体多种生理功能方面扮演着举足轻重的角色，涵盖消化、睡眠及血压调节等。然而，VIP同时展现出免疫抑制的特性。当VIP与免疫细胞，尤其是那些过度表达VIP的癌细胞发生相互作用时，会显著削弱邻近T细胞对这些癌细胞的攻击能力。通过应用针对该受体的特异性拮抗剂来阻断这一通路，我们能够重振T细胞的功能，使其重新获得消灭癌细胞的能力。

在针对白血病和胰腺癌的小鼠模型实验中，我们已取得了极具前景的初步成果。在此基础上，我们研发了一种长效肽拮抗剂，该药物仅需每周给药一次，大幅提升了患者的用药便利性。这一创新药物有望与当前针对PD-1、TIM-3或LAG-3等不同通路的免疫检查点疗法形成良好的互补效应。我们的VIP拮抗剂不仅可与其他免疫检查点抑制剂联合应用，还可与低剂量化疗方案相结合，以更有效地诱导T细胞对癌细胞的攻击，为癌症治疗开辟新的途径。

Oncology Frontier-Hematology Frontier：Compared to the known immune checkpoints such as CTLA-4 and PD-1, what are the unique features of the novel immune checkpoint pathways? Do these unique features imply greater therapeutic potential for the novel immune checkpoint pathways?What does this mean for cancer patients?

Dr.Edmund K Waller: We've identified a novel immune checkpoint pathway mediated by a small neuronal peptide called VIP. VIP has an important role in regulating many physiological functions in the body, including digestion, sleeping, and blood pressure. But it is immunosuppressive when it interacts with immune cells, particularly cancer cells that overexpress VIP, and it limits the ability of T cells in their neighborhood to attack them. By blocking this pathway with antagonists to the receptor, we can reinvigorate T cell function and allow them to destroy cancer.We've seen very promising results against leukemia and pancreatic cancer in mouse models. We've developed a long-acting form of a peptide antagonist that can be given weekly. We think this will complement existing immune checkpoint therapies that target different pathways, such as PD-1, TIM-3, or LAG-3. Our drug, the VIP antagonist, may be given in combination with these other immune checkpoint pathways, or with low doses of chemotherapy to induce T cell attack on cancer.

Q3

新型免疫检查点通路的研究是否面临特定的挑战或难题？您和您的团队是如何克服这些挑战的？

Edmund K Waller教授：当我们初次涉足这一研究领域时，尚未存在高效能的VIP受体拮抗剂。鉴于此，我们投入了大量时间与精力，对各种肽序列进行了详尽的筛选，并精心设计和构建了一种效力更为显著的受体拮抗剂。然而，我们面临的第二个重大挑战在于肽的半衰期极为短暂。为解决这一问题，我们创新性地将肽与免疫球蛋白重链区域进行了偶联，从而实现了每周仅需给药一次的便捷性。推进至临床试验阶段，我们遭遇了第三个挑战，即需要进行深入的毒理学与药代动力学研究。

幸运的是，在美国联邦政府小企业创新研究（SBIR）计划的慷慨资助下，我们正稳步朝着这一目标迈进。此外，我们还携手一家知名企业，共同创立了Cambium Oncology公司，该公司目前正积极筹措资金，以全力支持我们的研究工作。

Oncology Frontier-Hematology Frontier：Are there specific challenges or difficulties in researching the novel immune checkpoint pathways? How have you and your team overcome these challenges?

Dr.Edmund K Waller: When we began this field, there were no potent VIP receptor antagonists. So we spent a lot of time screening different peptide sequences and designing and building a more effective receptor antagonist. The second challenge we had was that peptides have a very short half-life. So we've coupled our peptide to the immunoglobulin heavy chain region so that it can be administered on a weekly basis. The third challenge is really moving towards clinical trial initiation, where we need to perform toxicology and pharmacokinetics studies in animal models. We are currently making progress in that path with support from the US federal government through SBIR grants. And in partnership with the company, we founded Cambium Oncology, which is currently raising money to support those studies.

总 结

Waller教授详细介绍了其团队在细胞与免疫治疗领域的最新研究成果，特别是关于新型免疫检查点通路VIP及其拮抗剂的研发。通过阻断VIP与免疫细胞的相互作用，团队成功重振了T细胞的功能，为癌症治疗开辟了新的途径。此外，该团队还研发出一种长效肽拮抗剂，仅需每周给药一次，大幅提升了患者的用药便利性。尽管在研发过程中面临诸多挑战，但在SBIR计划的资助下，团队正稳步推进毒理学与药代动力学研究，并积极筹措资金，以全力支持后续的临床试验与研发工作。我们期待Waller教授团队能够取得更多突破性的成果，为癌症患者带来福音。

来源：肿瘤瞭望