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June 20, 2008 — 一位进展性黑色素瘤，并且有淋巴结与肺转移病患，在接受使用自身T细胞的实验性疗法后发生戏剧化的转变，不但如此，两年后肿瘤仍是消退的；这篇案例报告发表在6月19日的新英格兰医学期刊上。
唯一的治疗就是输注CD4+ T细胞，这些细胞先前从病患身上移出，并在实验室中大量繁殖。这位52岁男性罹患再发性黑色素瘤，对于高剂量干扰素阿法、高剂量间白素或切除没有反应，之后在腹股沟淋巴结与单边肺脏转移，输注T细胞两个月后，使用正子摄影（PET）或断层扫瞄（CT）检查再也看不到肿瘤，在最近一次的后续追踪中，病患的疾病已经两年没有再发。
主要研究者、西雅图华盛顿Fred Hutchinson癌症研究中心的Cassian Yee医师评论，我们对这些CD4+细胞的抗肿瘤效果与反应时间感到惊讶，她向Medscape肿瘤学表示，这些病患罹患进展性疾病且对治疗反应不佳，一般而言预期存活时间都不超过一年。
她指出，这是个剂量增加研究，我们主要并不是要针对治疗反应。我们进一步对这个病例进行研究，发现CD4+ T细胞在持续输注后仍然存活，且这位病患产生对其他肿瘤抗原的反应；其他8位病患也接受同样的治疗方式，部分病患疾病趋于稳定。
Yee医师附带表示，在这位病患身上看到的结果是成功的，但我们需要在较大型的研究中确认这项结果；她指出，目前正在计划更大型的研究，但这将会是非常有限的研究；她解释，增加T细胞数目是项很复杂的过程，且耗费时间（超过4个月），因此仅有少数病患纳入研究。
这些是令人印象深刻的数据，将能引领之后更进一步的进展。
来自佛州坦伯市H. Lee Moffitt癌症中心，未参与此研究的Jeffrey Weber医师表示，这些来自杰出研究者以及团队令人印象深刻的数据，可能引领更进一步的进展；他向Medscape肿瘤学表示，这些研究强化了刚在萌芽、与正在发展使用T细胞作为适应性癌症免疫疗法领域研究的热情。
华盛顿特区乔治城大学Lombardi综合癌症中心的Louis Weiner医师提醒，这类的研究不全然有效；他在同一篇期刊的论点文章中写道，无论如何，这项全新策略的成功以及清楚的免疫作用机转，指出了癌症适应性免疫疗法可行的新方向。
【过程是复杂且昂贵的】
Yee医师评论，增加T细胞数目的过程是非常复杂且昂贵的，此外，这些T细胞都是病患自体制造的，我们希望未来可以将这个过程流程化，但这仍将是非常耗费人力的。
Yee医师表示，这个过程需要很多资源与特殊的训练，因此并不容易重复进行；我认为，对这个领域有兴趣的研究者需要先建立与完成基础架构，才能于临床上使用这些细胞产品，同时，若是这些是他们机构愿意投入研究的话，再决定是否进行。
病患表示接受了50亿个复制后且表现特定之黑色素瘤相关NY-ESO抗原的CD4+ T细胞；这些细胞在病患体内存留了至少80天。
即使这位病患的所有肿瘤细胞中，仅有50~75%表现NY-ESO-1抗原，整个肿瘤在输注T细胞后萎缩；研究者推论病患的免疫反应扩大，且开始攻击其他抗原细胞；后续追踪检验显示T细胞具有对抗两种其他抗原的活性（MAGE-3与MART-1）。
Yee医师解释，CD4+ T细胞会制造他们自身的生长因子，且攻击自己的肿瘤细胞，但是它们也会吸引其他作用者细胞，包括CD8 T细胞，来增加免疫反应；她表示，或许这是为什么我们看到这位病患身上免疫反应对抗其他抗肿瘤抗原反应扩大的原因。然而，目前并不清楚这是否是他有完全反应的原因。
Weiner医师评论，在这个病例中，输注CD4+ T细胞可以对抗肿瘤引发的免疫抑制反应，但这并不全然如此；他提醒，这可能必须在病人个体身上证明治疗标的免疫抑制反应的机转。
Weiner医师高声质疑这些研究发现是否是海市蜃楼、绿洲，或是目的地的初景；他写道，时间将会回答一切，但是我质疑我们还没接近目的地，只是在视线可及的范围；对癌症免疫疗法而言，末日游戏已经展开。
Yee医师与其同事表示无相关资金上的往来；他们的研究由国家健康机构与许多癌症研究基金会赞助。Weiner医师表示接受Amgen与Eisai研究机构的经费赞助。Weber医师与Bristol-Myers Squibb及Medarex公司共同拥有一项专利。
Case Report of Advanced Melanoma Disappearing After T Cell Therapy
By Zosia Chustecka
Medscape Medical News
June 20, 2008 — One patient with advanced melanoma and metastases in the lymph nodes and lung made a dramatic recovery and was still in complete remission 2 years later, after an experimental treatment using his own T?cells. The case report was published in the June 19 issue of the New England Journal of Medicine.
The only treatment was an infusion of CD4+ T?cells, which had been removed from the patient earlier and vastly expanded in the laboratory. The 52-year-old man had recurrent melanoma, which had not responded to high-dose interferon-alfa, high-dose interleukin-2, or excision. He had developed metastases in the groin lymph nodes and in 1 lung. Two months after the T?cell infusion, the tumors were no longer visible on positron emission tomography (PET) or computed tomography (CT) scans. He was still disease-free 2 years later, at his most recent follow-up.
"We were surprised by the antitumor effects of these CD4+ T?cells and the duration of response," commented lead investigator Cassian Yee, MD, from the Fred Hutchinson Cancer Research Center, in Seattle, Washington. Usually such a patient, with progressive disease refractive to therapy, would be expected to survive for less than a year, she told Medscape Oncology.
"This was a dose-escalation study, so we were not looking for responses primarily," she said. "We investigated him more closely and found that the CD4+ T?cells persisted long-term after infusion, and he developed a response to other tumor antigens." Eight other patients have been treated with the same method, but Dr. Yee said it is too early to report on them yet. There have been some other responses, although not as dramatic, and some cases of stable disease, she said.
"For this patient we were successful, but we would need to confirm the effectiveness of this therapy in a larger study, " Dr. Yee added. A larger trial is planned, but it will still be a very limited study, she said. The process of expanding the T?cells is complex and time consuming (>4 months), so only a fraction of patients would be eligible, she explained.
These are impressive data?.?.?., which could lead to significant further advances.
These are "impressive data from an excellent investigator and team, which could lead to significant further advances," said Jeffrey Weber, MD, from the H. Lee Moffitt Cancer Center, in Tampa, Florida, who was not involved with this study. "This is fine work that strengthens enthusiasm for the nascent and developing field of adoptive immunotherapy of cancer using T?cells," he told Medscape Oncology.
"This type of approach will not always work," warned Louis Weiner, MD, from the Lombardi Comprehensive Cancer Center at Georgetown University, in Washington, DC. Nevertheless, "the success of this novel strategy and the clear immune mechanisms of action point to feasible new directions for adoptive cellular therapy of cancer," he writes in a Perspective article in the same issue of the Journal.
Process is Complex and Expensive
The process by which the T?cells were expanded is complex and expensive, Dr. Yee commented, and the T?cells are custom-made for each patient. "We hope to streamline the process in the future, but it will still be labor intensive."
The process "requires a lot of resources and specialized training, so it is not easy to duplicate," Dr. Yee noted. "I think researchers who are interested will need to establish an infrastructure first that allows for the clinical use of cell products, and then decide if this is something their institution is willing to invest in."
The patient described received a dose of 5?billion cloned CD4+ T?cells with specificity for the melanoma-associated NY-ESO antigen.
The cells persisted for at least 80 days in the patient's body.
Even though the NY-ESO-1 antigen was expressed in only 50% to 75% of all the tumor cells in this patient, the entire tumor regressed after the infusion. The researchers postulate that the patient's immune response broadened and began attacking other antigens as well; follow-up tests showed T?cells active against 2 other antigens (MAGE-3 and MART-1).
Dr. Yee explained that CD4+ T?cells make their own growth factors and attack tumor cells themselves, but they also recruit other effector cells, including CD8 T?cells, to mount an immune response. "Perhaps that is why we saw a broadening of the immune response to other tumor antigens in this patient," she said. However, she added, "it is not clear if this is the reason that he had a complete response."
In this case, the CD4+ T?cells that were infused were able to overcome tumor-derived immunosuppression, but this will not always be the case, Dr. Weiner commented. "It may prove necessary to therapeutically target immune-suppression mechanisms on an individualized basis," he warned.
Dr. Weiner wondered aloud whether these findings represent a mirage, an oasis, or an early sighting of the destination? "Time will tell, but I suspect that if the destination is not yet at hand, it is in sight," he writes. For cancer immunotherapy, he said, the "end game has begun."
Dr. Yee and colleagues have disclosed no relevant financial relationships; their research was supported by the National Institutes of Health and several cancer-research foundations. Dr. Weiner has reported receiving research grants from Amgen and Eisai Research Institute. Dr. Weber shares a patent with Bristol-Myers Squibb and Medarex.
N Engl J Med. 2008;358:2698-2703 and 2664-2665.