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July 4, 2008 —根据一项初期研究结果显示，基因重组人类介白素（r-hIL）-7可以提升因为淋巴球数目减少而造成免疫力不全病患的免疫反应。
这项于6月23日线上发表在实验医学期刊的第一期临床试验结果显示，当对癌症病患投予时，rhIL-7诱发CD4+与CD8+ T细胞多株延展性增殖，这接着增加了循环T细胞受体的多变性，这些效应主要是透过增加周边T细胞循环、与增强细胞存活而致。
因为细胞毒性治疗造成淋巴球数目减少，或是HIV感染，会使免疫反应显著变弱；扮演增强生理免疫力的一个角色，IL-7可以回复T细胞的数目。历经免疫力严重下降达需要重新生成新生T细胞的病患，一般CD4+ T细胞数目回复的时间需要18到24个月，且可能仅发生在40到45岁以下的成人；因此，作者表示，若能加速或是促进老年病患不同的T细胞回复，可能可以有很多的临床用途。
马里兰班赛斯达国家癌症机构癌症研究中心实验性移植与免疫学部门的资深医师Claude Sportes医师表示，我们知道IL-7在动物身上可以增加肿瘤疫苗效果，因此这是个热门的研究领域，但这不仅仅是个肿瘤疫苗，令人欣慰的是，在不久的将来，我们将会有一个针对它如何增强抗病毒与其他免疫功能的研究，特别是对于老年病患。
IL-7在动物模式进行的初期研究显示，对于T细胞免疫重构有显著的效果，这显然也会增强老鼠对于疫苗的作用与记忆反应；在临床前模式，IL-7疗法能够增强抗肿瘤反应，当这样的反应与抗肿瘤疫苗并用时，可能可以改善存活率。
Sportes医师在一项访谈中表示，在老年病患身上，以IL-7治疗可以使得表现型回复免疫力；一般来说，这可以改善疫苗反应，而在肿瘤学中，则是改善肿瘤疫苗反应。
rhIL-7的应用可以是非常多的，目前有许多很有潜力的治疗应用；但是，就像在医学领域经常发生的，刚开始时可以是非常有潜力的，但最后可能是令人失望的。
【第一个使用在人类的研究】
这项第一期临床研究是第一个使用在人类的研究，Sportes医师与其同事评估IL-7治疗对于16位病患淋巴球的反应，这些病患年龄介于20到71岁之间，且罹患非血液、非淋巴对治疗反应不佳之癌症；使用的剂量是根据过去老鼠与灵长类研究推算得来，分别是3、10、30与60 μg/kg，每两天皮下注射一次，维持14天，共8个剂量。
他们发现，在短暂的下降后，循环中的T淋巴球数目与CD4+和CD8+ T细胞会随着剂量增加而增加；在最高剂量时，CD4+细胞增加将近300%，而CD8+ T细胞增加超过400%；整体而言，治疗诱发广泛性的T细胞循环，且可以扩张人类体内T细胞数量并维持T细胞功能。
Sportes医师表示，以rhIL-7治疗似乎比rhIL-2好，增加的T细胞保有显著的功能，且CD4+ T细胞扩张并不会伴随着T调节细胞不成比例地增加，这样的现象已经在使用rhIL-2治疗后发现；过去的数据显示，对人类活体投予IL-2，对于CD8 + T细胞数目没有太大影响，然而，rhIL-7对于CD8+ T细胞扩张的效应，至少和对CD4+ T细胞的相同。
研究者表示，rhIL-7增加T细胞受体多变性，虽然这显然选择性地扩张CD4+ 最近的胸腺迁移细胞、新生细胞与中央记忆族群细胞，但对于作用者T细胞并没有相同的作用。
Sportes医师表示，临床试验的详细内容，将会是另一篇文献的焦点；但是其耐受性良好，且我们将进行标准剂量测试。
【“免疫恢复”特性】
作者表示，rhIL-7对于具有免疫恢复特性的T细胞生长因子显然是有效的，表示这对于许多因为年龄、化学治疗与感染疾病等因子造成免疫功能不全的宿主，在增强其免疫力上是有效的。
在免疫系统完整与缺失的病患身上，rhIL-7增强，对于弱抗原反应、以及增加T细胞循环而不扩张T调节细胞的能力，可能是接受癌症化学治疗以及/或是慢性感染病患临床上值得探索的。
这项研究由国家卫生研究院校内研究计划、国家癌症机构（NCI）、与癌症研究中心赞助。NCI及rhIL-7新药持有者与制造厂商Cytheris公司正式的合作才能完成此项研究。Sportes医师表示没有相关资金上的往来。其中三位作者与Cytheris公司有资金上的往来。
IL-7 Therapy Boosts Immune Response in Cancer Patients
By Roxanne Nelson
Medscape Medical News
July 4, 2008 — Data from a preliminary study suggest that recombinant human interleukin (r-hIL)-7 can enhance and broaden immune responses in patients with impaired immunity due to lymphocyte depletion.
The results of the phase 1 trial, published online June 23 in The Journal of Experimental Medicine, showed that when given to cancer patients, rhIL-7 induced a dramatic polyclonal prolonged expansion of CD4+ and CD8+ T cells, which in turn caused a significant broadening of circulating T cell receptor repertoire diversity. These effects were mediated primarily through an increase in peripheral T cell cycling and augmented cell survival.
Lymphopenia induced by cytotoxic chemotherapy, or pathologies such as HIV infection, can significantly weaken immune function; as a physiologic immuno-enhancer, IL-7 can enhance the restoration of T cells. CD4+ T cell recovery in adults who have experienced severe depletion requires the reemergence of a pool of naive T cells, which generally takes 18 to 24 months and might only occur in people younger than 40 to 45 years. Thus, the authors note, a strategy that can accelerate or promote the recovery of a widely diverse T cell repertoire in older people might be useful for a large number of clinical applications.
"We know that IL-7 can enhance tumor vaccines in animals, so that would be a clear avenue of research," said lead author Claude Sportes, MD, senior staff clinician at the National Cancer Institute's Center for Cancer Research, Experimental Transplantation and Immunology Branch, in Bethesda, Maryland. "But it wouldn't only have to be tumor vaccines. Hopefully we will have a trial underway in the not-too-distant future looking at how it can enhance anti-viral and other immunizations, particularly in the elderly."
Treatment with IL-7 therapy exerted a marked effect on T cell immune reconstitution during preliminary trials with animal models. It also appeared to augment effector and memory responses to vaccination in mice; in preclinical models, IL-7 therapy was able to augment anti-tumor responses that might improve survival when combined with anti-tumor vaccines.
"In older individuals, therapy with IL-7 could lead to a rejuvenation of the phenotype," explained Dr. Sportes in an interview. "This in turn can lead to better vaccine responses in general and, in oncology, better tumor vaccine responses."
The implications for rhIL-7 are potentially vast, and there are many promising therapeutic avenues. "But as often happens in medicine," he cautioned, "things can be very promising at this stage and then fizzle out."
First Human Trial
In this phase 1 dose-escalation study, the first initiated in a human population, Dr. Sportes and colleagues evaluated the effects of IL-7 therapy on human lymphocytes in 16 patients, between the ages of 20 to 71 years, with nonhematologic, nonlymphoid refractory cancer. The doses, extrapolated from previous mouse and primate studies, were 3, 10, 30, and 60 μg/kg, and were administered by subcutaneous injection every other day for 14 days, for a total of 8 doses.
They found that after a very transient decrease, the numbers of circulating lymphocytes and CD4+ and CD8+ T cells increased in a dose-dependent manner. At the highest dose levels, increases approached 300% for CD4+ and exceeded 400% for CD8+ T cells. Overall, the treatment induced widespread T cell cycling and was able to expand the T cell pool in human patients while preserving T cell function.
Treatment with rhIL-7 also seems to have advantages over rhIL-2, explained Dr. Sportes. The expanded T cells retained significant functional capacity, and the CD4+ T cell expansion was not accompanied by a disproportionate increase in T regulatory cells, a phenomenon that has been observed after rhIL-2 therapy. Previous data have shown that in vivo IL-2 administration in humans has minimal effects on CD8+ T cell numbers, whereas rhIL-7 effects on CD8+ T cell expansion are at least comparable to the effects on CD4+ T cells.
The researchers noted that rhIL-7 increases T cell receptor repertoire diversity, and that although it appears to selectively expand CD4+ recent thymic emigrants, naive cells, and central-memory populations, it did not have the same effect on effector T cells.
The details of the clinical trial will be the focus of a separate paper, said Dr. Sportes. "But it was well tolerated and we went to full-dose escalation."
"Immune Rejuvenating" Properties
rhIL-7 appears to be an effective T cell growth factor with "immune rejuvenating" properties, suggesting that it is effective in augmenting immune reactivity in hosts with impaired immunity due to any number of factors, including age, chemotherapy, and infectious disease, the authors note.
In patients with both intact and deficient immune systems, the capacity of rhIL-7 to augment responses to weak antigens and to increase T cell cycling without expanding T regulatory cells might be clinically exploitable in the context of immunotherapy regimens for cancer and/or chronic infection, they write.
The study was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute (NCI), and the Center for Cancer Research. It was made possible through a formal collaboration between the NCI and Cytheris Inc., the investigational new drug holder and manufacturer of rhIL-7. Dr. Sportes has disclosed no relevant financial relationships; 3 of his coauthors have reported financial interests in Cytheris.
J Exp Med. Published online before print June 23, 2008.