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2015-12-17
个性化Neoantigen肿瘤疫苗与Nivolumab联用临床试验开启

20151215日,Neon Therapeutics开始其个性化Neoantigen肿瘤疫苗NEO-PV-01Nivolumab联用的1b期临床试验,主要评价用于黑色素瘤、烟民非小细胞肺癌(注意是吸烟者)和膀胱癌的安全性、耐受性和初步疗效。


Neon Therapeutics是在哈佛大学和麻省理工学院研究基础上创立的癌症疗法公司,基于Neoantigen概念,201510Neon获得了5500万美元的首轮融资。随后,疫苗初创公司Gritstone Oncology基于此策略也获得了1.02亿美元的A轮投资。肿瘤疫苗一度黯淡,借着Neoantigen的策略,大有翻身的架势。


【NeonTherapeutics and Bristol-Myers Squibb Enter Clinical Trial Collaboration】
Phase 1b Study to Combine Neon Therapeutics’ Personalized Neoantigen CancerVaccine with Opdivo

December 15, 2015 08:30 AM Eastern Standard Time

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Neon Therapeutics, an immuno-oncologycompany developing neoantigen-based therapeutic vaccines and T cell therapiesto treat cancer, today announced a clinical trial collaborationwith Bristol-Myers Squibb. The collaboration will evaluate the combinationof Neon Therapeutics’ proprietary personalized neoantigen vaccine, NEO-PV-01,and Opdivo (nivolumab),a PD-1 immune checkpoint inhibitor.

Neon Therapeutics’ lead program, NEO-PV-01, is a fully personalizedneoantigen vaccine based on DNA mutations from patients’ individual tumors.Opdivo is a human programmed death receptor-1 (PD-1) blocking antibody thatbinds to the PD-1 receptor expressed on activated T-cells. The Phase 1bclinical trial will evaluate the safety, tolerability and preliminary efficacyof NEO-PV-01 inpatients receiving Opdivo in melanoma, smoking-associated non-small cell lungcancer and bladder cancer. The trial also will evaluate neoantigen-specificimmune responses in peripheral blood and tumor tissue, as well as otherindicators of immune response such as PD-L1 expression. Neon Therapeutics plansto initiate the study at multiple clinical sites in theU.S.in 2016.

“We are excited to be working with Bristol-Myers Squibb, a proven leader inimmuno-oncology,” said Cary Pfeffer, M.D., interim chief executive officer ofNeon Therapeutics. “We believe this collaboration will accelerate thedevelopment of fully personalized neoantigen therapies, and provide additionaldata around the potential synergy of complementary immune-mediated mechanismsof action.”

The study will be conducted by Neon Therapeutics. Additional details of thecollaboration were not disclosed.

About Neon Therapeutics
Neon Therapeutics is an immuno-oncology company focused on developing noveltherapeutics leveraging neoantigen biology to treat cancer. A neoantigen-basedproduct engine will allow Neon to develop further treatment modalitiesincluding next-generation vaccines and T cell therapies targeting bothpersonalized as well as shared neoantigens. Neon Therapeutics’ lead program isa personalized neoantigen vaccine that builds upon years of research anddevelopment at the Broad Institute and Dana-Farber Cancer Institute, and isalready in multiple clinical trials. For more information, please visit www.neontherapeutics.com.


Neoantigen肿瘤疫苗联合免疫检查点抑制剂的出发点

免疫检查点抑制剂能够阻断PD-1和配体PD-L1之间的作用,从而解放T细胞,进而消灭肿瘤。但免疫检查点抑制剂只对一部分人有效,比如肺癌病人只有20-30%经过治疗后,肿瘤缩小了。问题出在哪里?


肿瘤细胞突变会产生新的表位(newepitope),即新生抗原(neoantigen),这些新生抗原与机体的正常抗原在结构上有很大不同,相当于给肿瘤细胞加上一个“标签”,neoantigen会触发免疫系统去相应这些异物抗原。突变越多,neoantigen就越多,也就越能刺激病人的T细胞发挥作用,进而免疫检查点抑制剂药物也才可能有用武之地。所以免疫卡控点抑制剂的作用机制就是保护和释放被肿瘤微环境所抑制的特异性肿瘤杀伤T淋巴细胞,是一个间接的过程,需要体内具有预存的能够识别肿瘤特异性靶点的T淋巴细胞。而对于体内本身不存在特异性T细胞,或细胞量过低的患者,即使给了checkpoint药也并不能杀伤肿瘤细胞,因为真正杀伤消灭肿瘤细胞的是特异性T细胞,checkpoint药只是解除了对特异性T细胞的抑制,却没有真正冲锋陷阵的战士。因此,有研究者就尝试把突变肿瘤表达的neoantigen做成个性化的肿瘤疫苗,进一步刺激病人的免疫系统产生积极反应。NEO-PV-01就是一种有助于增强人体自然反应的个性化疫苗,为患者度身定制,专门以他们各自的肿瘤抗体为目标,能够教育患者体内的细胞如何辨别和攻击肿瘤抗原。


来自Genentech的科学家在2015年的Science上发表了关于neoantigen策略的评论,题目也颇有深意《Neo approach to cancervaccines》,文中写道:“…the case that only a minority of patients benefit from these agents. It seems likely that among patients who do not respond or respond poorly to immunotherapies, there will be individuals who lack preexisting antitumor T cell responses. In principle, this situation can be addressed with antitumor vaccines,a strategy that has yet to yield much success despite decades of effort. The recent finding that tumor-specific mutations (neoantigens) may drive potent antitumor responses has provided hope and prompted renewed interest in the field…


个性化肿瘤疫苗原理


Neoantigen是现在很受追捧的概念,与PD1药物联合,我们期望能解决大部分对免疫检查点抑制剂无效病人的问题。


Nivolumab与其他疫苗联合布局总结见下表