Using genetic engineering techniques, investigators at the Johns Hopkins Kimmel Cancer Center and its Ludwig Center, the Lustgarten Laboratory and Bloomberg~Kimmel Institute for Cancer Immunotherapy have designed a novel type of cell to recognize and fight cancer.

To produce the cells, 称为Co-STAR(共刺激合成t细胞受体和抗原受体)细胞, 研究人员将身体通常用来抵御入侵者的四种细胞的遗传成分结合起来，从T细胞中制造出一种强大的新细胞:T细胞受体(TCRs), antibodies from B cells, MyD88 from white blood cells called monocytes, and CD40 from dendritic and other cells. The TCR and antibody components served as an “invader detecting device,” recognizing cancer cells as foreign, 由这个混合探测器触发的“警报”由MyD88和C40组件增强.   

In laboratory studies, 联合stars在试管和小鼠体内对生长的人类癌细胞产生了持续的抗肿瘤反应. A description of the work was published July 10 in Science Translational Medicine.

基于T细胞的疗法是治疗晚期癌症最有前途的方法之一，也是研究的热点, explains lead study author Brian Mog, M.D., Ph.D., an internal medicine resident at Brigham and Women’s Hospital in Boston. 当这项研究进行时，他是约翰霍普金斯大学医学院的一名医学和研究生.

However, TCR and CAR (chimeric antigen receptor, usually using antibody as the detector), which are aimed at stimulating an immune response by activating T cells, each has limits. The combination of the two can overcome these limitations.

“We needed to make a new type of cell, 因为我们试图针对一种叫做人类白细胞抗原肽的抗原, 它们是癌细胞内突变蛋白的肽片段通过称为hla的肽持有蛋白在细胞表面显示出来,” Mog explains. 他们的具体目标是含有p53的R175H突变的肽(p53的第175个氨基酸从精氨酸突变为组氨酸)。, displayed on the HLA-A2 allele (gene variation). This is the most common mutation in the tumor suppressor protein p53, which is in turn the most commonly mutated gene in human cancers. 

However, 这些抗原在癌细胞上的数量非常少(只有1到10), and the classic CAR format would not be able to react to such a small amount.  “我们的目标是将CAR格式的一些优势与T细胞上的天然T细胞受体的优势结合起来, supplemented with additional signaling boosters, so that they could fight cancers more effectively,” Mog says.

该团队经过多轮工程设计才得出最终设计, 在试管模型癌细胞系中测试它们的受体，然后在小鼠癌症模型中测试. 最终的Co-STAR T细胞能够在试管中连续杀死人类癌细胞.  When tested in mouse models of cancer, Co-STARs induced a robust, T细胞的长期增殖，能够诱导深度缓解, and often cure, human cancer cells growing in mice. By contrast, 更传统的T细胞或CAR - T细胞不能在体外根除癌细胞，只能在小鼠体内暂时控制肿瘤, with the cancers re-emerging days later. 

Brian的研究结果表明，Co-STAR T细胞结合了免疫细胞通常抵抗感染的许多特征的优势，使它们能够有效地杀死小鼠模型中的癌细胞,” says co-senior investigator Bert Vogelstein, M.D., Clayton Professor of Oncology, 霍华德休斯医学研究所研究员兼路德维希中心联合主任. “Co-STARs address some, but certainly not all, T细胞疗法面临的挑战，但肯定值得继续研究.”

“I was, honestly, incredibly surprised that the Co-STARs worked so well in mice, 考虑到我在四年中产生了如此多不同类型的T细胞，这些T细胞只能减缓小鼠癌症的生长。”Mog补充道. “Witnessing those cures was a very exciting moment.”

Study co-authors were Nikita Marcou, Sarah DiNapoli, Alexander Pearlman, Tushar Nichakawade, Michael Hwang, Jacqueline Douglass, Emily Han-Chung Hsiue, Stephanie Glavaris, Katharine Wright, Maximilian Konig, Suman Paul, Nicolas Wyhs, Jiaxin Ge, Michelle Miller, P. Aitana Azurmendi, Evangeline Watson, Drew Pardoll, Sandra Gabelli, Chetan Bettegowda, Nickolas Papadopoulos, Kenneth Kinzler and Shibin Zhou of Johns Hopkins.

The work was supported by the Virginia and D.K. Ludwig Fund for Cancer Research, the Lustgarten Foundation, the Commonwealth Fund, 布隆伯格慈善基金会和布隆伯格-坎摩尔癌症免疫治疗研究所, 国家卫生研究院(NH)癌症中心支持基金P30 CA006973, NIH grants (T32 GM136577, T32 AR048522, 1R21 AI176764, and K08CA270403), the National Institute of General Medical Sciences (grant T32GM148383), 国家癌症研究所(资助T32CA153952和R37CA230400)和白血病的奖励 & Lymphoma Society Translational Research Program, the American Society of Hematology, Swim Across America translational cancer research, the Jerome Greene Foundation, the Cupid Foundation, the Stephen and Renee Bisciotti Foundation, 哈林顿学者创新基金和风湿病研究基金会.

约翰霍普金斯大学已经提交了与本文中描述的技术相关的专利申请, Wright, Douglass, Mog, Hwang, Pearlman, Papadopoulos, Kinzler, Vogelstein, Gabelli, Pardoll and Zhou are listed as inventors. Vogelstein, 金兹勒和帕帕多普洛斯是茁壮成长早期检测公司的创始人(金兹勒和帕帕多普洛斯是该公司的顾问), an Exact Sciences company. Vogelstein, Kinzler, Papadopoulos和Zhou持有Exact Sciences公司的股权，也是Clasp Therapeutics公司的创始人或顾问，并拥有该公司的股权, NeoPhore, and Personal Genome Diagnostics. Vogelstein, Kinzler和Papadopoulos是Haystack Oncology和Cage Pharma的创始人或顾问，并拥有其股权. Papadopoulos is a consultant to Vidium. Vogelstein是Catalio Capital Management的顾问，并持有该公司股权. Zhou has a research agreement with BioMed Valley Discoveries. Bettegowda is a consultant to DePuy Synthes, Bionaut Labs, Haystack Oncology, Galectin Therapeutics, and Privo Technologies, and is a co-founder of OrisDX and Belay Diagnostics. Gabelli is a founder and holds equity in AMS LLC. Konig received consulting fees from Argenx, Atara Biotherapeutics, Revel Pharmaceuticals, Sana Biotechnology and Sanofi. Douglass previously consulted for Hemogenyx Pharmaceuticals. Paul is a consultant for Merck, owns equity in Gilead and received payment from IQVIA and Curio Science. Pardoll reports grant and patent royalties through Johns Hopkins from BMS, a grant from Compugen, stock from Trieza Therapeutics and Dracen Pharmaceuticals, and founder equity from Potenza. He is a consultant for Aduro Biotech, Amgen, AstraZeneca (MedImmune/Amplimmune), Bayer, DNAtrix, Dynavax Technologies, Ervaxx, FLX Bio, Rock Springs Capital, Janssen, Merck, Tizona and Immunomic Therapeutics. Pardoll is also on the scientific advisory boards of Five Prime Therapeutics, Camden Nexus II和windmill以及Dracen Pharmaceuticals的董事会成员. Wright and Gabelli are current or former employees of Merck Sharp & Dohme and may own stock or stock options. The companies named above, as well as others, 是否从约翰霍普金斯大学获得了与本文中描述的工作相关的先前描述的技术的许可. Vogelstein, Kinzler和Papadopoulos是其中一些技术的发明者. 这些技术的许可将与向发明人以及约翰霍普金斯大学支付的股权或特许权使用费相关联. 本论文所述工作的专利申请可由约翰霍普金斯大学提出. 所有这些安排的条款都由约翰霍普金斯大学根据其利益冲突政策进行管理.