华人科学家发现：肿瘤疫苗加低剂量化疗治疗胰腺癌的新方法

Pancreatic tumors 'reprogrammed' by new vaccine

　

　

　

 

来自马里兰州巴尔的摩约翰霍普金斯大学医学院的研究人员发现，一种疫苗和低剂量化疗的结合可能会使胰腺癌对免疫疗法产生影响。这些发现意义重大，因为通常情况下，这些癌症对免疫疗法没有反应，不到5%的患者在诊断后存活了5年。

 

“胰腺癌是一种恶性肿瘤,通常缺乏肿瘤浸润效应淋巴细胞和被认为是“非免疫原性”肿瘤,“Lei Zehng博士说,助理教授西德尼Kimmel综合癌症中心的肿瘤学和手术Skip Viragh胰腺癌研究中心,在约翰霍普金斯大学的临床护理。

 

郑博士解释说:“胰腺癌唯一的治疗方法是彻底的外科切除，大约80%的患者在手术后5年内复发并死于该疾病，这表明需要采取有效的策略。”

 

郑博士的团队发表在《癌症免疫学研究》上的一项新研究，旨在评估胰腺导管腺癌(PDAC)患者对新疫苗的反应。

　

　

 

这种名为GVAX的疫苗是由约翰霍普金斯大学(Johns Hopkins)的研究人员伊丽莎白·贾菲(Elizabeth Jaffee)博士开发的，目的是“重新编程”肿瘤，使其包括能够抗击癌症的免疫系统T细胞。为了实现这一点，GVAX是由经过修饰的受辐照的肿瘤细胞组成的，这些细胞被用来为病人的肿瘤招募免疫细胞。

 

Jaffee博士说，这种疫苗有可能将许多不同类型的肿瘤转化成一种对免疫疗法敏感的状态。这些包括免疫调节化疗药物，如环磷酰胺，它的目标是“Treg”——一种抑制抗癌T细胞免疫反应的免疫细胞。

 

该研究小组招募了59名患有PDAC的患者，他们的研究从2008年到2012年进行。一组患者自己接受了GVAX，另一组患者接受了疫苗加200 mg/m2的环磷酰胺，另一组接受了疫苗加100 mg口服环磷酰胺(每日，交替数周)。

 

疫苗产生的淋巴聚集物可以调节免疫细胞的激活。

 

所有患者在接种疫苗后2周进行手术摘除肿瘤。研究人员通过分析被切除的肿瘤发现，疫苗导致了一种叫做“第三级淋巴聚集物”的结构的产生。

　

图示胰腺的位置。

 

通过对肿瘤的分析，研究人员发现这种疫苗引起了一种叫做“三级淋巴聚集”的结构。

 

这些聚集物——在39个没有疾病的患者中形成的33个——被发现有助于调节免疫细胞的激活和运动，而且它们不会自然地出现在这些类型的肿瘤中。

 

“这表明肿瘤内部的淋巴细胞结构发生了重大的重组，”郑博士总结道。

Jaffee博士说，这些聚集物可以“真正改变肿瘤内部的免疫平衡，建立一个环境来激活良好的T细胞以对抗癌症，”并补充说，“这些T细胞将被教育去识别特定肿瘤环境中的癌症蛋白。”

 

更仔细地看，研究人员还发现肿瘤已经成为免疫原体，这意味着肿瘤周围的免疫细胞现在有能力攻击癌细胞。

 

由于“效应T细胞”与“调节T细胞”的比例增加，肿瘤已成为免疫原性的。研究人员发现，在病人身上发现的效应细胞与调节性T细胞的比例越大，病人存活的机会就越高。

 

郑博士说:“我们的研究已经提出了一种新的模式，可以开发出一种更有效的免疫疗法，用于治疗像胰腺癌这样的传统非免疫原性肿瘤。”“我们下一步将研究免疫疗法，包括癌症疫苗和增强‘良好’免疫调节信号或阻断‘不良’免疫调节信号的治疗。”

 

Pancreatic tumors 'reprogrammed' by new vaccine

Published      Wednesday 18 June 2014 By David McNamee

Researchers from the Johns Hopkins University School of Medicine in Baltimore, MD, have discovered that a combination of a vaccine and low-dose chemotherapy may make pancreatic cancer susceptible to the effects of immunotherapy. These findings are significant because, typically, these cancers do not respond to immunotherapy, with fewer than 5% of patients surviving 5 years after diagnosis.

 

"Pancreatic cancer is one of a number of malignancies that typically lack tumor-infiltrating effector lymphocytes and have been considered 'nonimmunogenic' neoplasms," says Dr. Lei Zehng, assistant professor of oncology and surgery at the Sidney Kimmel Comprehensive Cancer Center and the Skip Viragh Center for Pancreatic Cancer Research and Clinical Care at Johns Hopkins.

 

"The only curative treatment for pancreatic cancer," Dr. Zehng explains, "is complete surgical resection, and approximately 80% of patients who undergo surgery relapse and die from the disease within 5 years, suggesting a need for effective strategies."

 

The new study from Dr. Zheng's team - published in Cancer Immunology Research - was intended to evaluate how patients with pancreatic ductal adenocarcinomas (PDAC) might respond to a new vaccine.

 

The vaccine, called GVAX, was developed by Johns Hopkins researcher Dr. Elizabeth Jaffee to "reprogram" tumors to include immune system T cells that are able to fight cancer. To accomplish this, GVAX is made of irradiated tumor cells that have been modified to recruit immune cells to the patient's tumor.

 

Dr. Jaffee says that the vaccine has the potential to convert many different types of tumors to a state where they are susceptible to immunotherapies. These include immune-modulating chemotherapy drugs such as cyclophosphamide, which targets "tregs" - a type of immune cell that suppresses the immune responses of the cancer-fighting T cells.

 

The team recruited 59 patients with PDAC for their study, which ran from 2008-2012. One group of patients received GVAX on its own, another group of patients received the vaccine plus 200 mg/m2 of cyclophosphamide, and another received the vaccine plus 100 mg oral doses of cyclophosphamide (daily, on alternate weeks).

 

Vaccine 'created lymphoid aggregates' that regulate immune cell activation

All patients underwent surgery to remove their tumors 2 weeks after receiving the vaccination. The researchers discovered from analyzing the excised tumors that the vaccine had caused the creation of structures called "tertiary lymphoid aggregates."

 

illustration showing location of the pancreas

Analyzing the tumors, the researchers discovered that the vaccine had caused the creation of structures called "tertiary lymphoid aggregates."

These aggregates - which formed in 33 of the 39 patients who remained disease free - were found to help regulate immune cell activation and movement, and they do not appear in these types of tumor naturally.

 

"This suggests that there has been significant reprogramming of lymphocyte structures within the tumor," concludes Dr. Zheng.

 

Dr. Jaffee says that these aggregates could "really shift the immunologic balance within a tumor, setting up an environment to activate good T cells to fight the cancer," adding that "such T cells would be educated to recognize the cancer proteins in that specific tumor environment."

 

Looking more closely, the researchers also found that the tumors had become immunogenic, which means the immune cells surrounding the tumor now had the ability to attack the cancer cells.

 

The tumors had become immunogenic because the ratio of "effector T cells" to "regulatory T cells" had increased. The researchers observed that the greater the ratio of effector to regulatory T cells found in a patient, the better that patient's chances of survival were.

 

"Our study has suggested a new model for developing more effective immunotherapy for traditionally nonimmunogenic tumors like pancreatic cancer," Dr. Zheng says. "We will next investigate immunotherapies that include both cancer vaccines and treatments that boost the 'good' immune-regulatory signals or block the 'bad' immune-regulatory signals."

 

Pancreatic tumors 'reprogrammed' by new vaccine  https://www.medicalnewstoday.com/articles/278400.php