药物有助于重编程巨噬细胞免疫细胞,抑制前列腺和膀胱肿瘤的生长
05/21/2024
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一种新的治疗方法,通过重新编程免疫细胞来促进抗肿瘤活性,有助于缩小小鼠难以治疗的前列腺癌和膀胱癌, according to research from the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy and Johns Hopkins Drug Discovery.
The study was published online May 3 in the journal Cancer Immunology Research, a journal of the American Association for Cancer Research.
帮助免疫系统识别和对抗肿瘤的免疫疗法已经彻底改变了对许多类型癌症的治疗. However, these therapies, 加速肿瘤细胞杀伤免疫细胞t细胞的产生和激活, 对侵袭性前列腺癌和膀胱癌无效吗. 肿瘤学领域一直在试图找出免疫疗法在这些癌症中更好地发挥作用的原因和方法, explains the study’s senior author, Jelani Zarif, Ph.D., Robert E. Meyerhoff是约翰霍普金斯大学肿瘤学教授和副教授. 扎里夫和他的同事怀疑免疫细胞巨噬细胞是罪魁祸首. Under some conditions, macrophages help tumors grow and suppress T-cell activity, hampering the immune response to cancers.
“我们的工作重点是将免疫抑制肿瘤相关巨噬细胞重新编程为抗癌免疫细胞,以增强对免疫疗法和其他标准治疗癌症疗法的治疗反应,” Zarif says.
The immune-suppressing macrophages rely on the amino acid glutamine. 扎里夫和他的同事先前证明,巨噬细胞前体细胞称为单核细胞,如果在没有谷氨酰胺的实验室环境中生长,就会发育成免疫激活的巨噬细胞. 相反,当单核细胞与谷氨酰胺一起生长时,它们变成免疫抑制巨噬细胞.
扎里夫和他的团队假设,阻断免疫细胞获取谷氨酰胺的药物将使巨噬细胞的平衡转向免疫刺激型,并有助于缩小肿瘤. 研究表明,一种叫做6-重氮-5-氧- l -去甲亮氨酸(DON)的药物可以使肿瘤中缺乏谷氨酰胺,从而使依赖谷氨酰胺生长的肿瘤缩小. 但这种药物作为癌症治疗药物的开发在几十年前就被放弃了,因为它对胃肠道系统有毒,并造成有害的副作用.
相反,扎里夫使用了一种由研究合著者开发的实验性谷氨酰胺阻断药物 Barbara Slusher, Ph.D., director of Johns Hopkins Drug Discovery, and Jonathan Powell, M.D., Ph.D.布隆伯格-坎摩尔癌症免疫治疗研究所前副主任. The drug, JHU083, 有一种叫做前药的分子可以被体内的细胞转化为活性药物吗. Specifically, JHU083 can only be turned into its active, glutamine-blocking form inside the tumor, 防止它在身体其他部位产生有害的副作用. Studies show the drug shrinks tumors, 减少癌症扩散,提高患皮肤癌动物的存活率, colon, blood and brain, as well as certain treatment-resistant breast cancers.
芭芭拉·斯拉什和她的团队改变了药物的化学成分,使其可以在全身无活性循环, and it only becomes active when it gets inside cancer cells,” Zarif explains. “Because the active form is only released to cancer cells, you can give a lower dose, further reducing the risk of side effects.”
扎里夫和他的同事们表明,JHU083阻断了谷氨酰胺在小鼠前列腺和膀胱肿瘤中的应用, reducing tumor growth and triggering tumor cell death. 它还将免疫抑制巨噬细胞重新编程为免疫增强巨噬细胞. The macrophages themselves started destroying tumor cells. 它们还帮助招募肿瘤杀伤t细胞和自然杀伤细胞进入肿瘤. Adding an immunotherapy called a checkpoint inhibitor, which boosts the activation of T-cells in tumors, did not increase the effects of JHU083. 扎里夫解释说,这可能是因为在jhu083治疗的肿瘤中已经有了很多抗肿瘤免疫活性.
“JHU083可能是一种很有前途的抗癌疗法,用于治疗含有免疫抑制巨噬细胞和太少t细胞的肿瘤,” he says. “对于对检查点抑制剂没有反应的肿瘤,它也可能是一种很有希望的药物.”
扎里夫计划与约翰霍普金斯大学的同事合作,在治疗难治性前列腺癌或膀胱癌患者身上开展JHU083的临床试验,看看它是否能缩小肿瘤并防止转移. 他们还想继续研究JHU083与其他治疗方法结合是否能提高其抗肿瘤的有效性.
The study’s other co-authors were Monali Praharaj, Fan Shen, Alex J. Lee, Liang Zhao, Thomas R. Nirschl, Debebe Theodros, Alok K. Singh, Xiaoxu Wang, Kenneth M. Adusei, Kara A. Lombardo, Raekwon A. Williams, Laura A. Sena, Elizabeth A. Thompson, Ada Tam, Srinivasan Yegnasubramanian, Edward J. Pearce, Robert D. Leone, Jesse Alt, Rana Rais and Drew M. Pardoll of Johns Hopkins.
这项工作得到了Bloomberg ~ Kimmel癌症免疫治疗研究所的部分支持, a Prostate Cancer Foundation Young Investigator Award, 国家卫生研究院/国家癌症研究所(资助K22 CA237623), 美国国立卫生研究院(拨款#R01CA283649和#R01CA229451)和马里兰州卷烟赔偿基金拨款(#FHB33CRF).
约翰霍普金斯大学已经提交了与Slusher在论文中描述的技术相关的专利申请, Powell, Leone, Rais and Alt are listed as inventors. 斯拉什、鲍威尔和莱斯也是德拉肯制药公司的联合创始人和顾问. 这些关系由约翰霍普金斯大学根据其利益冲突政策进行管理.
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