2012年10月9日 訊 /生物谷BIOON/ --在一項新的臨床II期試驗中,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,,在進行干細胞移植之后,,在發(fā)育早期進行一種新的療法使得免疫系統(tǒng)更容易靶向多發(fā)性骨髓瘤細胞,從而有望提供持續(xù)的保護以便抵抗多發(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,,論文標題為“”。這項試驗是由Amir Toor教授領(lǐng)導(dǎo)完成的,。
在這項多期療法中,,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。阿扎胞苷強迫癌細胞表達被稱作癌癥睪丸抗原(cancer testis antigen, CTA)的蛋白,,而免疫系統(tǒng)細胞T淋巴細胞將這種蛋白識別為外來物,。來那度胺然后促進T淋巴細胞產(chǎn)生。利用一種被稱作自體淋巴細胞灌注(autologous lymphocyte infusion, ALI)的過程,研究人員從病人體內(nèi)提取出T淋巴細胞并接受這兩種藥物處理,,然后在病人接受干細胞移植來恢復(fù)這些干細胞的正常功能之后,,再將這些T淋巴細胞移植回病人體內(nèi)。
如今,,在干細胞移植之后,,這些T淋巴細胞能夠識別癌細胞為外來物質(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)每個細胞都在它們的表面上表達蛋白,,而免疫細胞能夠像條形碼那樣掃描這些蛋白以便確定這些細胞是否正常的或者它們是外源性的。因為多發(fā)性骨髓瘤細胞是從骨髓中產(chǎn)生的,,因此免疫系統(tǒng)細胞不能將它們從正常的健康細胞區(qū)分開來,。阿扎胞苷定會改變多發(fā)性骨髓瘤細胞的條形碼,從而導(dǎo)致免疫系統(tǒng)細胞攻擊它們,。”
這項臨床試驗的目標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胞灌注結(jié)合在一起進行治療,??偣灿?4名病人成功地完成這項研究性藥物療法,其中13名病人還成功地進行干細胞移植,。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)性骨髓瘤細胞增加表達CTA蛋白,研究人員在臨床試驗中對接受治療之前和之后的病人體內(nèi)提取的骨髓活組織進行實驗室分析,。接受測試的每名病人過量表達多種CTA蛋白,,這意味著這種治療方法成功地強迫癌細胞表達這些被免疫系統(tǒng)識別的靶標。
Toor說,,“人們可能在任何開展干細胞移植的機構(gòu)里相當廉價地重復(fù)我們設(shè)計的這種療法,。我們計劃在多發(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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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.