Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression.
Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression.
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DOI：
10.1158/1078-0432.ccr-11-1347
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发表时间：
2011-10-01
期刊：
影响因子：
--
通讯作者：
Rosenberg SA
中科院分区：
文献类型：
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作者：
Parkhurst MR;Riley JP;Dudley ME;Rosenberg SA
肿瘤浸润淋巴细胞（TIL）的过继性转移可介导转移性黑色素瘤的消退。然而，许多癌症患者不适合这种治疗，因为他们的TIL不能充分扩增，或者因为他们的肿瘤失去了抗原和/或主要组织相容性复合体（MHC）分子的表达。自然杀伤（NK）细胞是大颗粒淋巴细胞，以非MHC限制性方式裂解肿瘤细胞。因此，我们开展了一项临床试验，以评估过继性转移自体NK细胞治疗不适合TIL治疗的癌症患者的疗效。
转移性黑色素瘤或肾细胞癌患者在接受一种淋巴细胞清除但非清髓性化疗方案后，接受过继性转移的体外激活的自体NK细胞治疗。对临床反应和过继性转移细胞的持久性进行了评估。
8名患者接受了平均4.7×10¹⁰（±2.1×10¹⁰）个NK细胞的治疗。输注的细胞在体外表现出高水平的裂解活性。尽管未观察到临床反应，但过继性转移的NK细胞似乎在转移后至少一周内持续存在于患者的外周循环中，在一些患者中可持续数月。然而，循环中持续存在的NK细胞关键激活受体NKG2D的表达水平显著降低，并且在体外不能裂解肿瘤细胞靶标，除非用白细胞介素 - 2重新激活。
持续存在的NK细胞在体外无需细胞因子重新激活即可介导抗体依赖性细胞介导的细胞毒性，这表明将过继性NK细胞转移与单克隆抗体给药相结合值得评估。
Adoptive transfer of tumor infiltrating lymphocytes (TIL) can mediate regression of metastatic melanoma. However, many patients with cancer are ineligible for such treatment because their TIL do not expand sufficiently or because their tumors have lost expression of antigens and/or MHC molecules. Natural killer (NK) cells are large granular lymphocytes that lyse tumor cells in a non-MHC restricted manner. Therefore, we initiated in a clinical trial to evaluate the efficacy of adoptively transferred autologous NK cells to treat patients with cancers who were ineligible for treatment with TIL. Patients with metastatic melanoma or renal cell carcinoma were treated with adoptively transferred in vitro activated autologous NK cells after the patients received a lymphodepleting but non-myeloablative chemotherapy regimen. Clinical responses and persistence of the adoptively transferred cells were evaluated. Eight patients were treated with an average of 4.7×1010 (± 2.1×1010) NK cells. The infused cells exhibited high levels of lytic activity in vitro. Although no clinical responses were observed, the adoptively transferred NK cells appeared to persist in the peripheral circulation of patients for at least one week post-transfer, and in some patients for several months. However, the persistent NK cells in the circulation expressed significantly lower levels of the key activating receptor NKG2D and could not lyse tumor cell targets in vitro unless reactivated with IL-2. The persistent NK cells could mediate antibody dependent cell-mediated cytotoxicity without cytokine reactivation in vitro which suggests that coupling adoptive NK cell transfer with monoclonal antibody administration deserves evaluation.