一項新的研究顯示，微小的納米顆粒比人類的頭髮寬度小得多，可能有助於人體自身的免疫系統對抗腫瘤。在小鼠實驗中，基於納米粒子的療法不僅消滅了原有的靶向乳腺癌腫瘤，而且還消除了身體其他部位的轉移。研究人員說，新療法的人體臨床試驗可能會在未來幾個月內開始。

尋找刺激免疫系統對抗腫瘤的藥物是癌症研究中最熱門的領域之一。被稱為T細胞的免疫哨兵通常徘徊於可疑的目標，如細菌侵入者和潛在的腫瘤細胞。如果他們認識到這一點，他們就會發出警報，誘導其他免疫細胞發起更大的反應。然而，T細胞的警覺可以通過所謂的免疫檢查點，即正常細胞表面上的其他蛋白質來抑制，這些蛋白質抑制免疫應答以防止對正常組織的有害自體免疫反應。腫瘤細胞通常會過度表達這些檢查點分子，對免疫系統的搜索進行剎車並摧毀工作。

為了克服這個問題，製藥公司開發了許多不同的抗體蛋白質，可以阻斷這些過度表達的檢查點分子，並使免疫系統能夠靶向腫瘤。在腫瘤附近存在大量T細胞的情況下，或者腫瘤細胞經歷了大量突變（這為免疫哨兵產生額外靶標）的情況下，T細胞將發出對癌症的完全免疫應答。這種癌症免疫療法可以為患者的生活增加額外的時間。

然而，現有的癌症免疫治療藥物僅在20％至30％的患者中起作用。紐約紀念斯隆凱特琳癌症中心的癌症免疫治療專家Jedd Wolchok說，在某些情況下，即使檢查點分子被阻斷，周圍的活性T細胞數量太少以發出免疫警報。他說，在其他人的研究中，腫瘤在其表面上沒有足夠的T細胞靶標，即所謂的腫瘤抗原。

但一個看似無關的難題提供了提高免疫療法效力的前景。腫瘤學家早就知道，在罕見病例中，在患者接受放射治療以縮小腫瘤後，免疫系統會產生積極的反應，不僅會消滅腫瘤，而且會在整個身體內轉移，而這些轉移尚未經過放射治療。研究人員現在認為，輻射有時會以一種將新抗原暴露於T細胞的方式殺死腫瘤細胞，並啟動它們靶向其他攜帶它們的腫瘤細胞，伊利諾斯州芝加哥大學的化學家Wenbin Lin說，這項研究的作者。

林想看看他是否可以用類似的方式使用無毒納米粒子來增強免疫系統的敏感性。納米顆粒本身通過免疫系統並不容易。如果它們太大，血液中的細胞稱巨噬細胞吞噬它們。血液蛋白傾向於包裹顆粒，促進其攝取。近年來，林的團隊設計了一種生產粒徑在20到40納米之間（納米為十億分之一米）的方法，這是一種最能夠避開巨噬細胞的範圍。他們還用聚乙二醇外殼包裹它們，這有助於它們在血液循環中更長時間地存活並進入靶細胞。最後，他們在內部結合了強大的光吸收氯基分子，將納米粒子轉變為腫瘤殺手。

在以前的研究中，研究小組發現，一旦注射到血流中，顆粒就能夠循環足夠長的時間，以在腫瘤內和腫瘤周圍找到路徑。而且由於腫瘤通常有一個泄漏的，形成不規則的脈管系統，這些顆粒傾向於在癌症組織部位滲出並被拾取並在腫瘤細胞內部內化。一旦納米顆粒被吸收，研究人員就會在腫瘤附近發射近紅外光。這種光被氯基分子吸收，然後激發附近的氧分子，產生一種高反應性的氧，稱為單線態氧，將附近的生物分子撕裂並殺死腫瘤細胞。

但這只是它的開始，林說。單態氧傾向於分裂腫瘤細胞，使許多新的腫瘤抗原暴露於稱為樹突細胞的免疫細胞，像警察執行拉網一樣，抓住抗原並將它們呈遞給T細胞以進行更仔細的檢查。通過這樣做，即使在附近沒有很多T細胞的情況下，它們也可以幫助免疫系統發揮強大的抗腫瘤作用。

2016年8月，Lin和他的同事在Nature Communications上報道說，當他們將納米粒子注入結腸癌小鼠的血液中以及檢查點抗體並用光轟擊腫瘤時，這種組合激發了動物的免疫系統破壞靶向結腸癌腫瘤以及其他地方的未治療腫瘤。然而，這些顆粒還攜帶標準的化學治療毒素來幫助殺死癌細胞。在他們目前的研究中，研究人員想看看這種方法是否可以與免疫反應一起工作。

這一次，林和他的同事們與患有乳腺癌的老鼠一起工作，乳腺癌是另一種通常不會對現有免疫治療藥物產生反應的癌症。再一次，他們將這些動物與他們的納米粒子一起注入檢查點抗體。但是這次他們的納米粒子不含任何額外的化學治療藥物。然後他們用紅外光轟炸腫瘤，並等待結果。幾乎在所有情況下，不僅是原發性乳腺癌腫瘤被破壞，而且肺部轉移也被消滅，他們在美國化學學會雜誌上報道。「我們驚訝地發現，如果沒有細胞毒素，你可以達到同樣的效果，」林說。

「這是一個經過深思熟慮的方法，數據很有趣，」Wolchok說，他沒有參與這項工作。他補充道，這種方法值得跟進人體試驗。林說，這樣的審判很快就會開始。芝加哥團隊已經組建了一家名為協調製藥公司（Coordination Pharmaceuticals），該公司已經募集了種子基金，以便在今年下半年的某個時候在人類進行早期試驗。

Nanoparticles awaken immune cells to fight cancer

Tiny nanoparticles, far smaller than the width of a human hair, might help the body』s own immune system fight tumors, a new study shows. In experiments with mice, the nanoparticle-based therapy not only wiped out the original targeted breast cancer tumors, but metastases in other parts of the body as well. Human clinical trials with the new therapy could begin within the next several months, researchers say.

The search for drugs that spur the immune system to fight tumors is one of the hottest fields in cancer research. Immune sentries, known as T cells, are normally on the prowl for suspicious looking targets, such as bacterial invaders and potential tumor cells. If they recognize one, they sound the alarm, inducing other immune cells to mount a larger response. However, the T cells』 alarm can be muted by so-called immune checkpoints, other proteins on the surface of normal cells that tamp down the immune response to prevent harmful autoimmune reaction to normal tissue. Tumor cells often over express these checkpoint molecules, putting the brakes on the immune system』s search and destroy work.

To overcome that problem, pharmaceutical companies have developed a number of different antibody proteins that block these overexpressed checkpoint molecules and enable the immune system to target tumors. In cases where there are lots of T cells in the vicinity of a tumor, or where tumor cells have undergone large numbers of mutations, which creates additional targets for immune sentries, T cells will signal a full-fledged immune response to the cancer. Such cancer immunotherapy can add extra years to patients』 lives.

However, existing cancer immunotherapy drugs work in only 20% to 30% of patients. In some cases, even when the checkpoint molecules are blocked that there are too few active T cells around to sound the immune alarm, says Jedd Wolchok, a cancer immunotherapy expert at the Memorial Sloan Kettering Cancer Center in New York City. In others, he says, tumors don』t display enough of the T cell』s targets, so-called tumor antigens, on their surface.

But a seemingly unrelated puzzle offered the prospect of boosting immunotherapy』s effectiveness. Oncologists have long known that in rare cases, after patients receive radiation therapy to shrink a tumor, the immune system will mount an aggressive response that wipes out not only the tumor, but metastases throughout the body that hadn』t been treated with the radiation. Researchers now think that irradiation sometimes kills tumor cells in a manner that exposes new antigens to T cells, priming them to target other tumor cells that carry them as well, says Wenbin Lin, a chemist at the University of Chicago in Illinois, and one of the authors of the current study.

Lin wanted to see whether he could use nontoxic nanoparticles to sensitize the immune system in a similar way. Getting the nanoparticles themselves past the immune system isn』t easy. If they』re too big, cells in the blood called macrophages gobble them up. And blood proteins tend to coat the particles, facilitating their uptake. In recent years Lin』s team devised a method to produce particles that are all between 20 and 40 nanometers in size (a nanometer is one-billionth of a meter), a range best able to elude macrophages. They also coated them with a polyethylene glycol shell, which helps them survive longer in blood circulation and enter target cells. Finally, on the inside they incorporated powerful light-absorbing, chlorine-based molecules that turn the nanoparticles into tumor killers.

In previous studies, the team found that once injected into the bloodstream, the particles are able to circulate long enough to find their way in and around tumors. And because tumors typically have a leaky, ill-formed vasculature, the particles tend to leak out at the site of cancer tissue and be picked up and internalized inside tumor cells. Once the nanoparticles are absorbed, the researchers shine near infrared light on the tumors. That light is absorbed by the chlorine-based molecules, which then excite nearby oxygen molecules, creating a highly reactive form of oxygen, known as singlet oxygen, that rips apart nearby biomolecules and kills the tumor cell.

But that』s only the start of it, Lin says. Singlet oxygen tends to rip apart tumor cells in a manner that exposes many new tumor antigens to immune cells called dendritic cells, which, like police executing a dragnet, grab the antigens and present them to T cells for closer inspection. By doing so they help the immune system mount a powerful antitumor response even in cases where there aren』t that many T-cells nearby.

In August 2016, Lin and his colleagues reported in Nature Communications that when they injected a version of their nanoparticles into the bloodstream of mice with colon cancer along with a checkpoint antibody and blasted the tumors with light, the combination sparked the animals』 immune systems to destroy both the targeted colon cancer tumors as well as untreated tumors elsewhere. However, those particles also ferried a standard chemotherapeutic toxin to help kill the cancer cells. In their current study the researchers wanted to see whether the approach would work with just the immune response.

This time Lin and his colleagues worked with mice with breast cancer, another form of cancer that often doesn』t respond to current immunotherapy drugs. Again, they injected the animals with their nanoparticles along with a checkpoint antibody. But this time their nanoparticles didn』t contain any additional chemotherapeutic drug. They then blasted the tumors with infrared light, and waited for the results. And in almost every case, not only was the primary breast cancer tumor destroyed, but metastases in the lung were wiped out as well, they report in the Journal of the American Chemical Society. 「We were surprised to find that without the cytotoxic agents, you can achieve the same effect,」 Lin says.

「This is a well thought out approach, and the data is interesting,」 says Wolchok, who was not involved in the work. The approach deserves to be followed up with human trials, he adds. Lin says such trials are likely to start soon. The Chicago team has already formed a company, called Coordination Pharmaceuticals, which has raised seed funds to launch an early stage trial in humans, likely sometime in the second half of this year.

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