成功CD19基因治療(免疫細胞治療)治療Relapsed ALL

美成功利用基因技术治疗白血病 发布时间：2013-4-18 来源：药品资讯网信息中心美国一项最新研究说，利用基因技术对免疫细胞进行改造后可以使它们更有效地杀灭癌症细胞，这种方法已被成功应用于治疗白血病，研究人员认为它对其他癌症可能同样有效。 美国斯隆—凯特林癌症研究中心等机构研究人员在新一期《科学·转化医学》杂志上报告说，利用基因技术改造免疫细胞T细胞，使其可以识别白血病细胞中名为CD19的蛋白质，并以此为突破点杀灭白血病细胞。 对5名患有急性淋巴细胞白血病的成年患者进行的试验显示，这种方法非常有效，其中1人体内的癌症迹象在接受8天治疗后即消除，所有5人病情得到显著缓解最长仅费时59天。这些患者此前曾接受过标准化疗，均没有彻底治愈而又复发。 研究报告主要作者雷尼尔·布伦琴斯表示，这种新方法的疗效惊人，可能会给白血病等癌症治疗带来深远影响。白血病俗称血癌，急性淋巴细胞白血病是其中死亡率较高的一种。研究人员认为，这种方法对其他一些类型的癌症可能同样有效，正计划开展相关试验。

神奇基因療法 8天治癒血癌 編譯中心綜合20日電March 21, 2013 06:00美國研究人員20日說，新的跡象顯示，利用基因療法操控免疫系統，很可能成為對抗癌症的有效策略。「華爾街日報」報導說，主持研究的紐約史隆─凱特林癌症中心的研究人員，對五名罹患致命血癌的病人進行實驗性療法，利用基因技術改變這些病人本身的免疫系統細胞，使其針對癌細胞發動攻擊，結果這些病人的病情迅速完全緩解。這項研究規模雖小，可是效果極為顯著，五個病人的癌症都被消除。有個病人接受治療才八天，體內的癌症跡象即完全消失。在「科學轉化醫學」期刊發表的研究報告說，這些年紀從23歲到66歲的急性淋巴性白血病(ALL)患者，都曾接受標準化學治療，可是病情復發。這類病人通常病勢會迅速惡化，存活展望很差。研究人員擷取他們體內免疫系統負責對付感染和疾病的T細胞，利用基因技術加以改造，讓它們專門攻擊存在ALL細胞內的CD19蛋白質，然後把經過改造的T細胞輸回病人體內，讓它們去獵殺血癌細胞。賓州大學研究人員2011年8月也曾提出報告，利用類似方法成功治癒一名慢性淋巴細胞白血病患者。對五名病人進行的新研究，發現他們接受治療最多59天，病情即完全緩解。兩名病情特別嚴重的病人，接受治療後反應特別強烈，發高燒和血壓劇降，必須送進加護病房。紐約史隆─凱特林癌症中心醫生布倫金斯(Renier Brentjens)說，這種強烈副作用反映兩人病情的嚴重性，以及他們對基因治療的急劇反應，而施用類固醇使他們的情況順利獲得控制。這種治療效用能夠持續多久還不得而知，因為有四個病人在病情緩解後接受骨髓移植治療，使他們有機會完全痊癒。布倫金斯說，他們需要做更多研究，以確定用這種技術治療血癌的最佳方式。研究人員也打算對各種癌症試用這種治療方法。

Novel T-Cell Therapies Lead to Remission in Aggressive ALL Fran LowryMar 29, 2013 In one report, published online March 25 in the New England Journal of Medicine, chimeric antigen receptor-modified T-cells produced complete remission in 2 children with relapsed chemotherapy-refractive ALL .In the other report, published in the March issue of Science Translational Medicine, 5 adults (23 to 66 years) with relapsed B cell ALL were treated with a different form of genetically altered T-cells. All 5 achieved complete remission within 59 days of treatment, and 1 achieved a complete response within 8 days of treatment.These remissions allowed 4 of the 5 adults to go on to bone marrow transplantation, which demonstrates the feasibility of using T-cell therapy as a "highly effective bridge" to potentially curative therapy with subsequent allogeneic hematopoietic stem cell transplantation, write the researchers, led by Renier J. Brentjens, MD, PhD, from the Memorial Sloan-Kettering Cancer Center in New York City."The results here are profound," Dr. Brentjens is quoted as saying in the Wall Street Journal. "It's a very promising step forward."

Hope for Children With Relapsed ALL One of the 2 children described, a 7-year-old girl, is alive and well with no evidence of cancer cells in her body 11 months after receiving an intravenous infusion of the bioengineered T-cells.The second child, a 10-year-old girl, also achieved a complete remission but suffered a relapse 2 months later when other leukemia cells appeared that did not harbor the specific cell receptor targeted by the novel T-cells. She subsequently died.

Dr. Stephan Grupp "This is a proof-of-concept report," said lead author Stephan Grupp, MD, PhD, director of translational research at the Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, and professor of pediatrics at the Perelman School of Medicine, University of Pennsylvania.The T-cells that Dr. Grupp's team used were obtained from each child and modified to create a type of chimeric antigen-receptor cell called CTL019. These cells are designed to seek and destroy the CD19 protein on the surface of certain B cells, killing the leukemia cells.The unique thing about these CTL019 cells is that when they are returned to the patient (by intravenous infusion), they multiply by the thousands. Importantly, they remain in the body for a very long time, Dr. Grupp told Medscape Medical News.In most of the trials to date, the T-cells are put into the patient and "not that much happens — the cells don't grow very much — perhaps because the cells are at the end of their life span.... What is strikingly different about our approach is that these cells grow very significantly, 10,000-fold," Dr. Grupp explained.However, while the CTL019 cells are eliminating the leukemia, they can also generate an overactive immune response, or cytokine release syndrome, causing a dangerously high fever, low blood pressure, and flu-like symptoms.

This occurred in the 7-year-old patient. "She became very sick and was in intensive care. When we did an analysis, we found that her interleukin [IL]-6 was very elevated," Dr. Grubb said.His team decided to use tocilizumab, a drug developed for rheumatoid arthritis that specifically targets IL-6, and within hours, the severe symptoms resolved."It was absolutely astonishing. We gave it to her in the evening and soon after her fever was gone, her oxygen requirement disappeared overnight, and her blood pressure difficulties disappeared. She was dramatically better in an extremely short period of time. Clearly, we learned from this little girl that targeting IL-6 can control the toxicity without interfering with the T-cells killing the tumor cells. The T-cells did their thing even after we treated them with this IL-6 blocking drug," Dr. Grubb said. In the second child, "a small number of her B cells did not express CD19, or expressed it at a very low level. The T-cells did not see them. She went into a complete remission, but relapsed with cells that no longer had CD19 on their surface," he explained.The emergence of tumor cells that no longer express the target indicates a need to target molecules in addition to CD19 in some patients with ALL, he noted.

Alternative to Bone Marrow Transplant? Overall, the current chemotherapy options to treat B cell ALL are good. "We are not targeting those patients right now," Dr. Grupp emphasized."This therapy is for children who have exhausted all other options and who are at the end of their rope. This is what T-cell therapy should look like if it is going to work. We are seeing T-cells behave the way that they have to if cell therapy is going to be a viable treatment for cancer. We're very excited about that," he said.Dr. Grupp noted that the work his group is doing is somewhat different than that done by Dr. Brentjens' group, although it, too, is very exciting."They are also seeing the cells grow in the patient, but their cells don't stick around long enough. They are basically trying to get patients into remission so that they can go on to bone marrow transplantation. We are trying to develop an alternative to bone marrow transplantation. I am a bone marrow transplanter by trade, and I'm looking for a way to put myself out of business.... We don't know which approach is right, but it's great that both are being tested," Dr. Grupp said.The study by Dr. Grupp's team was funded by the National Institutes of Health, the Leukemia and Lymphoma Society, and the Alliance for Cancer Gene Therapy. The University of Pennsylvania and Novartis have an exclusive global research and licensing agreement to further study and commercialize T-cell therapies using chimeric antigen-receptor technologies. Novartis has exclusive rights to CTL019. Dr. Grupp has filed a patent on aspects of toxicity. The study by Dr. Brentjens' team was supported by the National Cancer Institute and Memorial Sloan-Kettering. Dr. Brentjens holds a patent on the engineered T-cell receptor.N Engl J Med. Published online March 25, 2013. Abstract