2012年10月9日 訊 /生物谷BIOON/ --在一項(xiàng)新的臨床II期試驗(yàn)中,，來自美國弗吉尼亞聯(lián)邦大學(xué)梅西癌癥中心(Virginia Commonwealth University Massey Cancer Center)的研究人員,，在進(jìn)行干細(xì)胞移植之后，在發(fā)育早期進(jìn)行一種新的療法使得免疫系統(tǒng)更容易靶向多發(fā)性骨髓瘤細(xì)胞,，從而有望提供持續(xù)的保護(hù)以便抵抗多發(fā)性骨髓瘤的惡化,。相關(guān)研究結(jié)果于2012年發(fā)表在British Journal of Haematology期刊上,，論文標(biāo)題為“”,。這項(xiàng)試驗(yàn)是由Amir Toor教授領(lǐng)導(dǎo)完成的。
在這項(xiàng)多期療法中,，研究人員聯(lián)合使用藥物阿扎胞苷(azacitidine)和來那度胺(lenalidomide)來治療多發(fā)性骨髓瘤病人,。阿扎胞苷強(qiáng)迫癌細(xì)胞表達(dá)被稱作癌癥睪丸抗原(cancer testis antigen, CTA)的蛋白，而免疫系統(tǒng)細(xì)胞T淋巴細(xì)胞將這種蛋白識(shí)別為外來物,。來那度胺然后促進(jìn)T淋巴細(xì)胞產(chǎn)生,。利用一種被稱作自體淋巴細(xì)胞灌注(autologous lymphocyte infusion, ALI)的過程，研究人員從病人體內(nèi)提取出T淋巴細(xì)胞并接受這兩種藥物處理,，然后在病人接受干細(xì)胞移植來恢復(fù)這些干細(xì)胞的正常功能之后,，再將這些T淋巴細(xì)胞移植回病人體內(nèi)。
如今,，在干細(xì)胞移植之后,，這些T淋巴細(xì)胞能夠識(shí)別癌細(xì)胞為外來物質(zhì)而能夠潛在性地抵抗多發(fā)性骨髓瘤復(fù)發(fā)。
Toor說,，“體內(nèi)每個(gè)細(xì)胞都在它們的表面上表達(dá)蛋白,，而免疫細(xì)胞能夠像條形碼那樣掃描這些蛋白以便確定這些細(xì)胞是否正常的或者它們是外源性的。因?yàn)槎喟l(fā)性骨髓瘤細(xì)胞是從骨髓中產(chǎn)生的,，因此免疫系統(tǒng)細(xì)胞不能將它們從正常的健康細(xì)胞區(qū)分開來,。阿扎胞苷定會(huì)改變多發(fā)性骨髓瘤細(xì)胞的條形碼，從而導(dǎo)致免疫系統(tǒng)細(xì)胞攻擊它們,。”
這項(xiàng)臨床試驗(yàn)的目標(biāo)是確定它是否是安全的,，甚至可能的話，將這兩種藥物服用與自體淋巴細(xì)胞灌注結(jié)合在一起進(jìn)行治療,?？偣灿?4名病人成功地完成這項(xiàng)研究性藥物療法，其中13名病人還成功地進(jìn)行干細(xì)胞移植,。最后,，4名病人產(chǎn)生完全的反應(yīng)，這就意味著不能檢測(cè)到微量的多發(fā)性骨髓瘤,，還有5名病人產(chǎn)生非常好的部分反應(yīng)從而導(dǎo)致他們的血液中的異常蛋白水平下降了90%,。
為了確定阿扎胞苷是否導(dǎo)致多發(fā)性骨髓瘤細(xì)胞增加表達(dá)CTA蛋白，研究人員在臨床試驗(yàn)中對(duì)接受治療之前和之后的病人體內(nèi)提取的骨髓活組織進(jìn)行實(shí)驗(yàn)室分析,。接受測(cè)試的每名病人過量表達(dá)多種CTA蛋白,，這意味著這種治療方法成功地強(qiáng)迫癌細(xì)胞表達(dá)這些被免疫系統(tǒng)識(shí)別的靶標(biāo)。
Toor說,，“人們可能在任何開展干細(xì)胞移植的機(jī)構(gòu)里相當(dāng)廉價(jià)地重復(fù)我們?cè)O(shè)計(jì)的這種療法,。我們計(jì)劃在多發(fā)性骨髓瘤病人體內(nèi)探索免疫療法的可能性以便為這種很難治療的疾病尋找出更加有效的治療方法。”(生物谷Bioon.com)
doi: 10.1111/j.1365-2141.2012.09225.x
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PMID:
Epigenetic induction of adaptive immune response in multiple myeloma: sequential azacitidine and lenalidomide generate cancer testis antigen-specific cellular immunity
Amir A. Toor1,*, Kyle K. Payne2, Harold M. Chung1, Roy T. Sabo3, Allison F. Hazlett1, Maciej Kmieciak2, Kimberly Sanford4, David C. Williams4, William B. Clark1, Catherine H. Roberts1, John M. McCarty1, Masoud H. Manjili
Patients with multiple myeloma (MM) undergoing high dose therapy and autologous stem cell transplantation (SCT) remain at risk for disease progression. Induction of the expression of highly immunogenic cancer testis antigens (CTA) in malignant plasma cells in MM patients may trigger a protective immune response following SCT. We initiated a phase II clinical trial of the DNA hypomethylating agent, azacitidine (Aza) administered sequentially with lenalidomide (Rev) in patients with MM. Three cycles of Aza and Rev were administered and autologous lymphocytes were collected following the 2nd and 3rd cycles of Aza-Rev and cryopreserved. Subsequent stem cell mobilization was followed by high-dose melphalan and SCT. Autologous lymphocyte infusion (ALI) was performed in the second month following transplantation. Fourteen patients have completed the investigational therapy; autologous lymphocytes were collected from all of the patients. Thirteen patients have successfully completed SCT and 11 have undergone ALI. Six patients tested have demonstrated CTA up-regulation in either unfractionated bone marrow (n = 4) or CD138+ cells (n = 2). CTA (CTAG1B)-specific T cell response has been observed in all three patients tested and persists following SCT. Epigenetic induction of an adaptive immune response to cancer testis antigens is safe and feasible in MM patients undergoing SCT.
