免疫疗法对转移性前列腺癌有效具有特定的免疫激活标记

尽管转移性去势抵抗前列腺癌（mCRPC）通常对免疫治疗的反应有限，在德克萨斯大学安德森癌症中心进行的II期试验中，一部分患者在接受伊匹利木单抗治疗后，其肿瘤中有活跃T细胞反应的预处理证据，其生存期延长。德州医学博士安德森癌症中心。

显微照片显示前列腺腺泡腺癌（前列腺癌的最常见形式）图片来源：维基百科

今天发表在《科学转化医学》上的结果表明，某些患有mCRPC的患者可能会受益于免疫检查点抑制剂，并提供用于鉴定该亚组的生物标志物。

“我们的结果表明，尽管前列腺癌的肿瘤突变负担很低，但免疫检查点阻滞仍可促进T细胞对肿瘤新抗原的反应，”泌尿生殖医学肿瘤学助理教授Sumit Subudhi博士说。“我们在受益最大的一部分患者中发现了特定的标志物，例如T细胞密度和干扰素-γ信号传导，这可能有助于提高我们选择接受检查点封锁治疗的患者的能力。”

与最强应答的癌症免疫关卡抑制剂，如黑色素瘤或肺癌的癌症，往往有高水平的底层基因突变，这导致生产突变蛋白，或新抗原的，可以由免疫系统识别为异常。前列腺癌的突变水平相对较低，并且存在的新抗原较少。

Subudhi 解释说，然而，在较大的III期临床试验中的一小群mCRPC患者对检查点抑制剂显示出了有利的结果，这驱使研究人员提出疑问：对于突变水平较低的肿瘤，检查点封锁是否可以刺激有效的免疫反应。

显微照片显示前列腺腺泡腺癌（前列腺癌的最常见形式）图片来源：维基百科

今天发表在《科学转化医学》上的结果表明，某些患有mCRPC的患者可能会受益于免疫检查点抑制剂，并提供用于鉴定该亚组的生物标志物。

“我们的结果表明，尽管前列腺癌的肿瘤突变负担很低，但免疫检查点阻滞仍可促进T细胞对肿瘤新抗原的反应，”泌尿生殖医学肿瘤学助理教授Sumit Subudhi博士说。“我们在受益最大的一部分患者中发现了特定的标志物，例如T细胞密度和干扰素-γ信号传导，这可能有助于提高我们选择接受检查点封锁治疗的患者的能力。”

与最强应答的癌症免疫关卡抑制剂，如黑色素瘤或肺癌的癌症，往往有高水平的底层基因突变，这导致生产突变蛋白，或新抗原的，可以由免疫系统识别为异常。前列腺癌的突变水平相对较低，并且存在的新抗原较少。

Subudhi 解释说，然而，在较大的III期临床试验中的一小群mCRPC患者对检查点抑制剂显示出了有利的结果，这驱使研究人员提出疑问：对于突变水平较低的肿瘤，检查点封锁是否可以刺激有效的免疫反应。

以下是原文：

Immunotherapy effective in metastatic prostate cancers with specific markers of immune activation

Although metastatic castration-resistant prostate cancer (mCRPC) typically has limited response to immunotherapy, a subset of patients with pretreatment evidence of active T-cell responses in their tumors experienced prolonged survival after following treatment with ipilimumab in a Phase II trial at The University of Texas MD Anderson Cancer Center.

The results, published today in?Science Translational Medicine, suggest that certain patients with mCRPC may benefit from immune checkpoint inhibitors and provide biomarkers for identifying this subgroup.

"Our results indicate that immune checkpoint blockade can instigate T-cell responses to tumor neoantigens despite a low tumor mutational burden in?prostate cancer," said lead author Sumit Subudhi, M.D., Ph.D., assistant professor of Genitourinary Medical Oncology. "We found specific markers among a subset of patients with the greatest benefit, such as T-cell density and interferon-γ signaling, that may help improve our ability to select patients for treatment with checkpoint blockade."

Cancers with the strongest responses to?immune checkpoint inhibitors, such as melanoma or lung?cancer, tend to have high levels of underlying gene mutations, which leads to production of mutation proteins, or neoantigens, that can be recognized as abnormal by the immune system. Prostate cancers have relatively low mutation levels and fewer neoantigens present.

However, small groups of mCRPC patients within larger Phase III trials have seen?favorable outcomes?to checkpoint inhibitors, explained Subudhi, which drove the researchers to ask whether effective immune responses could be stimulated by checkpoint blockade in tumors with low mutation levels.

To investigate this question, the research team launched the Phase II trial in collaboration with MD Anderson's immunotherapy platform, which is co-led by corresponding author Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology. The platform is part of the institution's Moon Shots Program, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patient's lives.

The trial enrolled 30 MD Anderson patients with mCRPC between January 2015 and May 2018. Of those, 29 received at least one dose of ipilimumab and were able to be included in the final analysis. Median follow-up after the first treatment was 45.5 months.

Across all patients, median progression-free survival (PFS) according to radiographic imaging was 3 months, and median overall survival (OS) was 24.3 months. Eight patients (28%) experienced grade 3 toxicities, the most common of which were dermatitis and diarrhea, and none experienced grade 4 or 5 toxicities.

The researchers noted a "favorable" cohort of nine patients with PFS greater than six months and OS greater than one year, and an "unfavorable" cohort of ten patients with PFS less than six months and OS less than one year. At the time of analysis, six (67%) patients from the "favorable" cohort were alive, with survival ranging between 33 and 54 months.

By comparing pretreatment samples from these two cohorts, the researchers identified markers associated with improved responses to checkpoint blockade. Those in the "favorable" cohort had a higher density of cytotoxic and memory T cells in the tumor as well as increased expression of interferon (IFN)-γ signaling.

Further, the researchers showed that T cells isolated from patients in the "favorable" cohort were capable of recognizing and responding to the neoantigens present in their tumor, whereas T cells from patients in the "unfavorable" group did not appear to have the same responses.

"We were encouraged to see that prostate cancers with a low mutational burden do in fact express neoantigens that elicit T-cell responses that lead to favorable clinical outcomes," said Sharma. "Our findings indicate that anti-CTLA-4 immune?checkpoint?therapy warrants additional studies in order to develop treatment strategies that may improve survival of patients with metastatic prostate cancer."

Moving forward, the authors plan to investigate this question in larger, multi-institutional studies to validate the findings of the current trial.

期刊信息：?科学转化医学??SK Subudhi等人，“ ipilimumab治疗前列腺癌患者后的新抗原反应，免疫相关性和良好的预后”，《科学转化医学》（2020）。stm.sciencemag.org/lookup/doi/…scitranslmed.aaz3577

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编译者/作者：Tark

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