一项小型临床试验的早期结果证明，一种新的细胞免疫疗法可能有效治疗转移性实体瘤。在这项试验中，美国国立卫生研究院 (NIH) 的研究人员对每位患者的正常白细胞（淋巴细胞）进行了基因改造，使其产生能够识别并攻击特定癌细胞的受体。这些初步研究结果来自已接受过多种早期治疗的转移性结直肠癌患者。个性化免疫疗法使一些患者的肿瘤缩小。退出免责声明并能够抑制肿瘤在长达七个月的时间内再次生长。该研究成果于2024年7月11日发表在《自然医学》杂志上。

一种细胞免疫疗法，即嵌合抗原受体 (CAR) T 细胞疗法，已被证明对某些血癌有效，另一种名为肿瘤浸润淋巴细胞 (TIL) 疗法，已被证明对转移性黑色素瘤有效。然而，美国国家癌症研究所 (NCI) 癌症研究中心 (CCR)的 Steven A. Rosenberg 医学博士表示，迄今为止，还未找到一种对任何其他实体癌都有效的细胞疗法。他与 CCR 外科分部的 Maria Parkhurst 博士共同领导了这项研究。

横截面 CT 图像显示患者左肺有转移性肿瘤（上图），治疗后无肿瘤（下图）。

“我们能够控制正在生长的转移性实体癌并使其消退，这表明新的细胞免疫治疗方法前景光明，”罗森伯格博士说道。“然而，重要的是要明白，这些发现还处于初步阶段，该方法需要在更多类型的实体癌中进一步完善和测试。”

这种新方法克服了细胞免疫治疗中的两个挑战：如何产生大量能够特异性识别癌细胞的 T 细胞，以及如何增强修饰后的 T 细胞在返回患者体内后的增殖能力。

对于研究中的每位患者，罗森伯格博士及其同事收集了患者肿瘤中的淋巴细胞。然后，他们利用复杂的分子表征技术识别并分离这些淋巴细胞上的受体（称为T细胞受体），这些受体可以识别每位患者肿瘤中的特定变化。在对这些受体进行基因测序后，他们利用逆转录病毒将受体的基因插入从每位患者循环血液中采集的正常淋巴细胞中。

经过基因改造的淋巴细胞随后在实验室中繁殖到数亿个，并注入患者体内，在那里它们表达肿瘤特异性 T 细胞受体并继续繁殖。

罗森伯格博士解释说：“通过提取极少数细胞中存在的天然 T 细胞受体，并将其放入我们拥有的大量正常淋巴细胞中（每一滴血液中就有一百万个），我们可以生成任意数量的抗癌细胞。”

作为一项更大规模二期临床试验的一部分，七名转移性结肠癌患者接受了实验性个性化细胞免疫疗法治疗。七名患者在接受细胞疗法前均接受了数剂免疫疗法药物派姆单抗（Keytruda），并在之后接受了另一种名为IL-2的免疫疗法药物。三名患者的肝脏、肺脏和淋巴结转移性肿瘤显著缩小，且疗效持续了四至七个月。疾病进展的中位时间为4.6个月。

罗森伯格博士指出，在三名对治疗有反应的患者中，有两名接受了源自细胞毒性 T 细胞的 T 细胞受体治疗，这些细胞主要负责杀死患病细胞。罗森伯格博士说，他的研究团队正在探索如何将 T 细胞受体放入正常淋巴细胞的亚型中，以提高其反应性。

结肠癌只是研究人员正在研究的众多实体肿瘤之一。该试验仍在进行中，受试者包括患有不同类型实体癌的患者。

“这仅仅是将正常淋巴细胞转化为能够治疗常见实体癌的细胞的第一步，”罗森伯格博士说。“这项研究表明，这是可能的。一旦你知道这是可能的，你就会努力去改进它。”

来自：https://www.cancer.gov/news-events/press-releases/2024/personalized-immunotherapy-shrinks-solid-tumors

Immunotherapy approach shows potential in some people with metastatic solid tumors

Early findings from a small clinical trial provide evidence that a new cellular immunotherapy approach may be effective in treating metastatic solid tumors. In the trial, researchers from the National Institutes of Health (NIH) genetically engineered normal white blood cells, known as lymphocytes, from each patient to produce receptors that recognize and attack their specific cancer cells. These initial findings are from people with metastatic colorectal cancer who had already undergone multiple earlier treatments. The personalized immunotherapy shrank tumors in some patientsExit Disclaimer and was able to keep the tumors from regrowing for up to seven months. The findings were published July 11, 2024, in Nature Medicine.

One form of cellular immunotherapy, chimeric antigen receptor (CAR) T-cell therapy, has already been shown to be effective against some blood cancers, and another, called tumor-infiltrating lymphocyte (TIL) therapy, has proven to be effective against metastatic melanoma. However, to date, a cellular therapy that’s effective against any other solid cancers has been elusive, according to Steven A. Rosenberg, M.D., Ph.D., of NCI’s Center for Cancer Research (CCR), who co-led the study with Maria Parkhurst, Ph.D., of CCR’s Surgery Branch.

“The fact that we can take a growing metastatic solid cancer and get it to regress shows that the new cellular immunotherapy approach has promise,” Dr. Rosenberg said. “However, it’s important to understand that these findings are preliminary and that the approach needs to be further refined and tested in more types of solid cancers.”

The new approach overcomes two challenges in cellular immunotherapy: how to produce large numbers of T cells that can recognize cancer cells specifically, and how to boost the ability of modified T cells to multiply once they’ve been returned to the patient.

For each patient in the study, Dr. Rosenberg and his colleagues collected lymphocytes present in the patient’s tumors. They then used sophisticated molecular characterization techniques to identify and isolate receptors on those lymphocytes, called T-cell receptors, that recognized specific changes in each patient’s tumor. After genetically sequencing those receptors, they then used a retrovirus to insert the genes for the receptor into normal lymphocytes collected from each patient’s circulating blood.

The genetically modified lymphocytes were then multiplied into the hundreds of millions in the laboratory and infused back into the patients, where they expressed the tumor-specific T-cell receptors and continued to multiply.

“By taking the natural T-cell receptors that are present in a very small number of cells and putting them into normal lymphocytes for which we have enormous numbers—a million in every thimbleful of blood—we can generate as many cancer-fighting cells as we want,” Dr. Rosenberg explained.

As part of a larger phase 2 trial, seven patients with metastatic colon cancer were treated with the experimental personalized cellular immunotherapy. All seven received several doses of the immunotherapy drug pembrolizumab (Keytruda) before the cell therapy and another immunotherapy drug called IL-2 afterward. Three patients had substantial shrinkage of metastatic tumors in the liver, lung, and lymph nodes that lasted for four to seven months. The median time to disease progression was 4.6 months.

Dr. Rosenberg noted that, of the three patients who responded to the treatment, two had received T-cell receptors derived from cytotoxic T cells, which are primarily responsible for killing diseased cells. Dr. Rosenberg said his research team is exploring how to put the T cell receptors into subtypes of normal lymphocytes to improve their reactivity.

Colon cancer is just one of many solid tumors the researchers are studying. The trial is still ongoing and includes patients with different types of solid cancers.

“It's just the very beginning of converting normal lymphocytes into cells capable of treating the common solid cancers,” Dr. Rosenberg said. “What this study shows is that it's possible. Once you know it’s possible, you work to improve it.”