针对肾癌和胰腺癌的新型免疫治疗方法即将出现吗？

两项小型临床试验中，针对肾癌和胰腺癌的新型免疫疗法显示出了良好的疗效。在两项试验中，这些疗法似乎能够阻止已成功切除肿瘤的患者的癌症复发。

这些治疗方法被称为治疗性癌症疫苗，因为它们可以帮助免疫系统消除现有的癌症。

图示为多个圆形、蓝色的 T 细胞正在攻击肿瘤（橙粉色、圆形、比 T 细胞大）

个性化新抗原治疗疫苗旨在教导免疫细胞（如 T 细胞（蓝色））专门识别肿瘤（粉色）。

图片来源：iStock/Design Cells

在这两项试验中，我们根据手术中采集的肿瘤样本进行深入的基因分析，为每位患者制定了专门的治疗方案。这些分析使研究团队能够识别每位患者癌细胞上的突变蛋白（即新抗原）。这些“流氓蛋白”就像激活的安全警报器，提醒免疫系统癌细胞是应该被杀死的威胁。

然而，由于各种原因，这套警报系统失效了。基于新抗原的治疗旨在填补这一漏洞，强化免疫系统，使其意识到任何携带这些突变蛋白的细胞都必须被清除。

在这两项研究中，患者在手术后的几个月内接受了多次个性化治疗。手术后进行治疗的目的是杀死身体其他部位残留的癌细胞，并可能建立一小群免疫细胞，用于识别并杀死未来出现的任何癌细胞。

在纪念斯隆凯特琳癌症中心进行的胰腺癌试验中，16 名患者中有 8 名对治疗产生了强烈的免疫反应，6 名患者仍然没有癌症，其中一些人在初次手术后已超过 3 年研究小组于 2 月 19 日在《自然》杂志上发表了研究报告。

这项由丹娜—法伯癌症研究所开展的肾癌试验纳入了9名患者。试验中无一例患者复发，其中4例患者在手术后3年多仍未出现癌症。退出免责声明根据 2 月 5 日《自然》杂志报道的研究结果。

在两项试验的许多参与者中，能够识别疫苗中所含目标新抗原的免疫细胞在最后一次治疗剂量数年后仍然存在于他们的血液中。而且这些治疗似乎是安全的，两项研究都报告了轻微的副作用。

开展这项研究的研究团队表示，他们对这些疗法的潜力持乐观态度。但他们也强调，需要进行更大规模的临床试验（目前已启动）来证实这些初步结果。

更少的突变？个性化肿瘤新抗原疫苗怎么样？

被称为免疫检查点抑制剂的免疫疗法药物通常用于治疗肾癌患者，主要是癌症已扩散或转移到全身的患者。

新抗原疫苗制造流程图解

患者肿瘤细胞中发现的新抗原构成了治疗疫苗的基础，可帮助免疫系统将这些细胞识别为应被杀死的威胁。

图片来源：改编自《自然》杂志 2023 年 5 月刊。https://doi.org/10.1038/s41586-023-06063-y。CC BY 4.0。

然而，对于胰腺癌患者来说，免疫疗法革命尚未到来。临床试验中，免疫疗法——无论是单独使用还是与其他疗法联合使用——都未能取得任何疗效，即使对于肿瘤可以通过手术切除的患者也是如此。

但肾癌和胰腺癌患者的肿瘤确实有一些共同点：它们通常没有太多的基因突变。这会带来问题，因为突变越少，癌细胞上引起免疫系统注意的肿瘤新抗原就越少。

然而，技术进步使得在任何类型的癌症中寻找潜在的新抗原以及预测哪些新抗原最有可能引起免疫系统的兴趣变得更加容易。

九名肾癌患者无复发

在肾癌试验中，研究团队在每位患者的肿瘤中识别出多达20种他们认为能够引发最强免疫反应的新抗原。然后，他们以化学方式合成突变蛋白质的小片段（或肽），用于每位患者的治疗。

手术后不久，每位患者每周接受一次治疗，持续一个月。他们还分别在约12周和20周后接受加强剂量治疗。五名参与者在每次治疗期间还接受了低剂量的免疫检查点抑制剂伊匹单抗（Opdivo） 。

NCI 的医学博士马克·鲍尔 (Mark Ball) 专门治疗肾癌，但并未参与该项试验，他表示，试验参与者的癌症均未复发，这一事实“令人鼓舞和兴奋”。

然而，鲍尔博士提醒道，对于可手术的肾癌患者来说，手术后存活数年甚至更长时间且癌症不复发的情况并不少见。因此，目前尚不清楚免疫治疗是否是该试验中没有出现复发的原因。

他继续说，证明这是治疗结果的“更令人信服的数据”来自对患者接受治疗后免疫系统行为的分析。

鲍尔博士说：“他们清楚地看到了针对治疗所针对的新抗原的非常强烈的免疫反应。”

研究人员报告称，这些免疫反应在每次服药后的数周内发生，并且许多患者在接受最后一次服药几年后仍然有能够识别目标新抗原的T 细胞。

“我们了解了癌症中哪些特定目标最容易受到免疫攻击，并证明这种方法可以产生持久的免疫反应，”该试验的首席研究员、医学博士、哲学博士、前丹娜法伯癌症研究所研究员、现耶鲁癌症中心研究员 David Braun 在一份新闻稿中表示。

胰腺癌患者的持久反应

在胰腺癌试验中，纪念斯隆凯特琳癌症中心的研究人员与德国公司BioNTech合作。在本次试验中，新抗原是利用mRNA技术制造的。

对于每位患者的疫苗，BioNTech 构建了多达 20 种目标新抗原的 mRNA，并为每位患者生产了最终的治疗药物，称为自基因西维美兰。

研究中的患者在第一次自体基因西维美兰剂量时接受单剂量免疫检查点抑制剂阿特珠单抗 (Tecentriq)，随后在几个月内接受多剂疫苗接种，最后接受四种药物化疗方案的短期疗程。

参加胰腺癌试验的 16 名患者中有 8 名对治疗有反应，研究人员将此定义为免疫系统已被成功刺激去攻击具有目标新抗原的细胞的证据。

在8名对治疗无反应的患者中，癌症复发的中位时间约为13个月。8名对治疗有反应的患者中，有2名最终出现复发，其余6名在约3年后仍处于无癌状态。

一些有响应的患者的 T 细胞在最后一次服药后长达 4 年内仍能识别目标抗原。

更大规模的临床试验将提供更多关于安全性、有效性的信息

在这两项研究中，患者仅经历了轻微的副作用。鲍尔博士表示，尤其对于可以通过手术切除的肾癌患者，安全至关重要。

他说，晚期肾癌患者“如果能延长生命，通常更愿意忍受一些（副作用）。”但对于那些可以通过手术切除肿瘤的患者来说，需要找到不同的平衡点。

“他们的癌症复发几率要低得多，”他说。他继续说道，要让这种基于免疫的疗法成为这些患者日常治疗的一部分，“我们需要一种耐受性良好且安全的疗法。”

未来几年内，我们将会看到更多关于此类治疗的效果和安全性的信息。

在丹娜—法伯试验早期结果的基础上，默克和 Moderna 正在进行一项中型临床试验，测试个性化新抗原疫苗作为可手术肾癌患者的辅助疗法。

目前，Genentech 和 BioNTech 正在进行一项试验，测试纪念斯隆凯特琳癌症中心试验中使用的相同 mRNA 疗法作为可通过手术切除肿瘤的胰腺癌患者的辅助治疗。

来自：https://www.cancer.gov/news-events/cancer-currents-blog/2025/neoantigen-vaccine-pancreatic-kidney-cancer

Are New Immune-Based Treatments for Kidney and Pancreatic Cancer on the Horizon?

New immune-based treatments for kidney and pancreatic cancer have shown promising results in two small clinical trials. In both trials, the treatments appeared to prevent cancer from returning in patients who had successful surgery to remove their tumors.

The treatments are called therapeutic cancer vaccines because they help the immune system eliminate an existing cancer.

In both trials, the treatments were made specifically for each patient based on intensive genetic analyses of their tumor samples collected during surgery. The analyses allowed the research teams to identify mutated proteins, known as neoantigens, on each patient's cancer cells. These rogue proteins can act like an activated security alarm to the immune system, alerting it that the cancer cells are threats that should be killed.

For different reasons, however, this alarm system fails. The neoantigen-based treatments are designed to step into this breach, reinforcing to the immune system that any cells displaying these mutated proteins must be eliminated.

In both studies, patients received multiple doses of their personalized treatments in the months following surgery. Giving the therapy after surgery is intended to kill any remaining cancer cells elsewhere in the body and potentially establish a small band of immune cells that can recognize and kill any cancer cells that pop up in the future.

Of the 16 patients in the pancreatic cancer trial, which was conducted at Memorial Sloan Kettering Cancer Center, 8 had a strong immune response to the treatment and 6 are still cancer-free, some more than 3 years after their initial surgeryExit Disclaimer, the study team reported February 19 in Nature.

The kidney cancer trial, conducted at Dana-Farber Cancer Institute, included nine patients. No patients in the trial have had a recurrence, including four who were still cancer-free more than 3 years after their surgeryExit Disclaimer, according to findings reported February 5 in Nature.

In many participants in both trials, immune cells that could recognize target neoantigens included in their vaccines were still in their blood several years after their last treatment dose. And the treatments appeared to be safe, with only mild side effects reported in both studies.

The research teams that conducted the studies said they are optimistic about the treatments’ potential. But they also stressed that larger clinical trials—which have already been launched—are needed to confirm these initial results.

Fewer mutations? How about personalized neoantigen vaccines?

Immunotherapy drugs known as immune checkpoint inhibitors are regularly used to treat people with kidney cancer, primarily patients with cancer that has spread, or metastasized, throughout the body.

For people with pancreatic cancer, however, the immunotherapy revolution has yet to arrive. In clinical trials, immune-based treatments—either alone or in combination with other therapies—have failed to have any impact, including in patients whose tumors can be removed with surgery.

But tumors in people with kidney and pancreatic cancer do share something in common: They usually don’t have many genetic mutations. And that’s a problem because fewer mutations mean fewer neoantigens on cancer cells to draw the immune system’s notice.

However, technological advances have made it easier to find potential neoantigens in any kind of cancer and to predict which neoantigens are most likely to pique the immune system’s interest.

Nine people with kidney cancer, no recurrences

In the kidney cancer trial, the research team identified up to 20 neoantigens in each patient’s tumor that they felt could generate the strongest immune response. They then chemically synthesized small chunks, or peptides, of the mutated proteins to use in each patient’s treatment.

Shortly after surgery, each patient received one treatment dose a week for a month. They also received booster doses approximately 12 and 20 weeks later. Five participants also received a low dose of the immune checkpoint inhibitor ipilimumab (Opdivo) with each treatment dose.

The fact that the cancer has not returned in any trial participants is “encouraging and exciting,” said NCI’s Mark Ball, M.D., who specializes in treating kidney cancer but was not involved in the trial.

Dr. Ball cautioned, however, that it’s not unusual for people with operable kidney cancer to live for several years or longer after surgery without their cancer coming back. So, it’s unclear if the immune-based treatment is responsible for the lack of recurrences in the trial.

The “more compelling data” that it is a result of the treatment, he continued, comes from the analysis of patients’ immune system behavior after receiving it.

“They were clearly seeing a very strong immune response” against the neoantigens targeted by the treatment, Dr. Ball said.

Those immune responses occurred within weeks of each dose, the researchers reported, and many patients still had T cells that could recognize the targeted neoantigens several years after receiving the last dose.

“We learned which specific targets in the cancer are most susceptible to immune attack and demonstrated that this approach can generate long-lasting immune responses,” said a lead researcher on the trial, David Braun, M.D., Ph.D., formerly of Dana-Farber and now at Yale Cancer Center, in a press release.

Lasting responses in people with pancreatic cancer

For the pancreatic cancer trial, the Memorial Sloan Kettering researchers partnered with the German company BioNTech. For this trial, the neoantigens were made using mRNA technology.

For each patient’s vaccine, BioNTech constructed mRNAs for up to 20 target neoantigens and manufactured the final treatment, called autogene cevumeran, for each patient.

Patients in the study were given a single dose of the immune checkpoint inhibitor atezolizumab (Tecentriq) at the time of their first autogene cevumeran dose, followed by multiple vaccine doses over several months, and finally a short course of a four-drug chemotherapy regimen.

Eight of the 16 patients in the pancreatic cancer trial responded to the treatment, which the researchers defined as evidence that the immune system had been successfully stimulated to go after cells with the target neoantigens.

Among the eight who did not respond to the treatment, the median time until their cancer returned was about 13 months. Two of the eight responders eventually had a recurrence and the other six are still cancer-free after about 3 years.

Some responders had T cells that could still recognize the target antigens up to 4 years after their last dose.

Larger clinical trials will provide more information about safety, efficacy

In both studies, patients experienced only mild side effects. Particularly in people with kidney cancer that can be removed with surgery, Dr. Ball said, safety is paramount.

People with advanced kidney cancer “are often more willing to tolerate some [side effects] if it means extending their life,” he said. But for those whose tumors can be removed with surgery, there’s a different balance to be struck.

“The odds that their cancer will recur are much lower,” he said. For an immune-based therapy like this to become part of everyday treatment for these patients, he continued, “we’re going to need something that’s very well tolerated and safe.”

More information on how well these types of treatments work and their safety should emerge over the next few years.

Building on the early results from the Dana-Farber trial, Merck and Moderna are conducting a medium-sized clinical trial testing a personalized neoantigen vaccine as an adjuvant therapy in people with operable kidney cancer.

And Genentech and BioNTech are currently running a trial testing the same mRNA-based therapy used in the Memorial Sloan Kettering trial as an adjuvant treatment in people with pancreatic cancer whose tumors can be surgically removed.