A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer.
A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer.
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DOI：
10.3109/14653249.2010.515582
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发表时间：
2011-01
期刊：
影响因子：
4.5
通讯作者：
Miller JS
中科院分区：
文献类型：
--
作者：
Geller MA;Cooley S;Judson PL;Ghebre R;Carson LF;Argenta PA;Jonson AL;Panoskaltsis-Mortari A;Curtsinger J;McKenna D;Dusenbery K;Bliss R;Downs LS;Miller JS
与来自健康个体的NK细胞相比，来自癌症患者的自然杀伤（NK）细胞表现出降低的细胞毒性。我们评估了同种异体NK细胞在复发性卵巢癌和乳腺癌中的肿瘤反应和体内扩增。患者接受淋巴细胞清除准备方案：氟达拉滨25 mg/m2 × 5次，环磷酰胺60 mg/kg × 2次，7例患者接受200 cGy全身照射（TBI）以增加宿主免疫抑制。输注前，将来自单倍相同相关供体的NK细胞产物在1000 U/mL白细胞介素（IL）-2中孵育过夜。在NK细胞输注后皮下给予IL-2（10 MU），每周3次，共6次，以促进扩增，定义为输注后14天，基于分子嵌合体和流式细胞术检测到≥ 100个供体来源的NK细胞/µL血液。入组了20例（14例卵巢，6例乳腺）患者。中位年龄为52岁（范围30-65岁）。平均NK细胞剂量为2.16 × 107个细胞/kg。NK细胞输注后7天，9/13例（69%）无TBI患者和6/7例（85%）TBI患者检测到供体DNA。与化疗前相比，在第+14天调节性T细胞（Treg）升高（P = 0.03）。预处理后血清IL-15水平升高（P = <0.001）。接受TBI的患者血液学恢复延迟（P = 0.014）。1例不可评价的患者体内NK细胞扩增成功。淋巴细胞清除化疗后单倍相合NK细胞的连续转移与短暂的供体嵌合体有关，并可能受到受体Treg细胞重建的限制。需要增强体内NK细胞持久性和扩增的策略。
Natural killer (NK) cells derived from patients with cancer exhibit diminished cytotoxicity compared with NK cells from healthy individuals. We evaluated the tumor response and in vivo expansion of allogeneic NK cells in recurrent ovarian and breast cancer. Patients underwent a lymphodepleting preparative regimen: fludarabine 25 mg/m2 × 5 doses, cyclophosphamide 60 mg/kg × 2 doses, and, in seven patients, 200 cGy total body irradiation (TBI) to increase host immune suppression. An NK cell product, from a haplo-identical related donor, was incubated overnight in 1000 U/mL interleukin (IL)-2 prior to infusion. Subcutaneous IL-2 (10 MU) was given three times/week × 6 doses after NK cell infusion to promote expansion, defi ned as detection of ≥ 100 donor-derived NK cells/µL blood 14 days after infusion, based on molecular chimerism and flow cytometry. Twenty (14 ovarian, 6 breast) patients were enrolled. The median age was 52 (range 30–65) years. Mean NK cell dose was 2.16 × 107 cells/kg. Donor DNA was detected 7 days after NK cell infusion in 9/13 (69%) patients without TBI and 6/7 (85%) with TBI. T-regulatory cells (Treg) were elevated at day +14 compared with pre-chemotherapy (P = 0.03). Serum IL-15 levels increased after the preparative regimen (P = <0.001). Patients receiving TBI had delayed hematologic recovery (P = 0.014). One patient who was not evaluable had successful in vivo NK cell expansion. Adoptive transfer of haplo-identical NK cells after lymphodepleting chemotherapy is associated with transient donor chimerism and may be limited by reconstituting recipient Treg cells. Strategies to augment in vivo NK cell persistence and expansion are needed.
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影响因子：
2.9
作者：
McKenna, D. H.;Sumstad, D.;Miller, J. S.
通讯作者：
Miller, J. S.
影响因子：
11.2
作者：
Carlsten, Mattias;Bjorkstrom, Niklas K.;Malmberg, Karl Johan
通讯作者：
Malmberg, Karl Johan
DOI：
10.1073/pnas.0408197102
发表时间：
2005-01-11
影响因子：
11.1
作者：
Chen, ML;Pittet, MJ;Khazaie, K
通讯作者：
Khazaie, K
影响因子：
45.3
作者：
Chan, JK;Lin, SS;Berman, ML
通讯作者：
Berman, ML
影响因子：
82.9
作者：
Curiel, TJ;Coukos, G;Zou, WP
通讯作者：
Zou, WP