Division of Blood and Marrow Transplantation, Stanford University School of Medicine, 300 Pastaur Drive, Stanford, CA 94305, USA.
Biol Blood Marrow Transplant. 2011 Nov;17(11):1679-87. doi: 10.1016/j.bbmt.2011.05.012. Epub 2011 May 25.
Donor leukocyte infusions induce remissions in some patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (HCT); however, graft-versus-host disease (GVHD) remains the major complication of this strategy. Cytokine-induced killer (CIK) cells are a unique population of cytotoxic T lymphocytes that express the CD3(+)CD56(+) phenotype and show marked up-regulation of the natural killer cell receptor NKG2D (CD314). CIK cells are non-major histocompatibility complex-restricted and NKG2D-dependent in target recognition and cytotoxicity. We explored the feasibility of ex vivo expansion of allogeneic CIK cells in patients with relapsed hematologic malignancies after allogeneic HCT. Eighteen patients (median age, 53 years; range, 20-69 years) received CIK cell infusions at escalating doses of 1 × 10(7) CD3(+) cells/kg (n = 4), 5 × 10(7) CD3(+) cells/kg (n = 6), and 1 × 10(8) CD3(+) cells/kg (n = 8). The median expansion of CD3(+) cells was 12-fold (range, 4- to 91-fold). CD3(+)CD56(+) cells represented a median of 11% (range, 4%-44%) of the harvested cells, with a median 31-fold (range, 7- to 515-fold) expansion. Median CD3(+)CD314(+) cell expression was 53% (range, 32%-78%) of harvested cells. Significant cytotoxicity was demonstrated in vitro against a panel of human tumor cell lines. Acute GVHD grade I-II was seen in 2 patients, and 1 patient had limited chronic GVHD. After a median follow-up of 20 months (range, 1-69 months) from CIK infusion, the median overall survival was 28 months, and the median event-free survival was 4 months. All deaths were due to relapsed disease; however, 5 patients had longer remissions after infusion of CIK cells than from allogeneic HCT to relapse. Our findings indicate that this form of adoptive immunotherapy is well tolerated and induces a low incidence of GVHD, supporting further investigation as an upfront modality to enhance graft-versus-tumor responses in high-risk patient populations.
供者白细胞输注可诱导某些血液恶性肿瘤患者在异基因造血细胞移植（HCT）后复发时缓解；然而，移植物抗宿主病（GVHD）仍然是该策略的主要并发症。细胞因子诱导的杀伤（CIK）细胞是一种独特的细胞毒性 T 淋巴细胞群，表达 CD3(+)CD56(+)表型，并表现出自然杀伤细胞受体 NKG2D（CD314）的显著上调。CIK 细胞在靶标识别和细胞毒性方面是非主要组织相容性复合物限制的，并且依赖于 NKG2D。我们探讨了在异基因 HCT 后复发的血液恶性肿瘤患者中体外扩增同种异体 CIK 细胞的可行性。18 名患者（中位年龄 53 岁；范围 20-69 岁）接受了递增剂量的 1×10(7)CD3(+)细胞/kg（n = 4）、5×10(7)CD3(+)细胞/kg（n = 6）和 1×10(8)CD3(+)细胞/kg（n = 8）的 CIK 细胞输注。CD3(+)细胞的中位扩增倍数为 12 倍（范围 4-91 倍）。收获细胞中 CD3(+)CD56(+)细胞代表中位数 11%（范围 4%-44%），中位扩增倍数为 31 倍（范围 7-515 倍）。收获细胞中 CD3(+)CD314(+)细胞表达的中位数为 53%（范围 32%-78%）。体外对一组人肿瘤细胞系显示出显著的细胞毒性。2 例患者出现急性 GVHD Ⅰ-Ⅱ级，1 例患者出现局限性慢性 GVHD。从 CIK 输注后中位随访 20 个月（范围 1-69 个月）后，中位总生存期为 28 个月，中位无事件生存期为 4 个月。所有死亡均归因于疾病复发；然而，输注 CIK 细胞后，5 例患者的缓解期长于异基因 HCT 至复发。我们的研究结果表明，这种形式的过继免疫疗法具有良好的耐受性，并引起低发生率的 GVHD，支持进一步作为增强高危患者群体中移植物抗肿瘤反应的一线治疗方式进行研究。
