Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Blood. 2012 Apr 26;119(17):3940-50. doi: 10.1182/blood-2011-10-387969. Epub 2012 Feb 3.
Cellular immune responses have the potential to elicit dramatic and sustained clinical remissions in lymphoma patients. Recent clinical trial data demonstrate that modification of T cells with chimeric antigen receptors (CARs) is a promising strategy. T cells containing CARs with costimulatory domains exhibit improved activity against tumors. We conducted a pilot clinical trial testing a "third-generation" CD20-specific CAR with CD28 and 4-1BB costimulatory domains in patients with relapsed indolent B-cell and mantle cell lymphomas. Four patients were enrolled, and 3 received T-cell infusions after cyclophosphamide lymphodepletion. Treatment was well tolerated, although one patient developed transient infusional symptoms. Two patients without evaluable disease remained progression-free for 12 and 24 months. The third patient had an objective partial remission and relapsed at 12 months after infusions. Modified T cells were detected by quantitative PCR at tumor sites and up to 1 year in peripheral blood, albeit at low levels. No evidence of host immune responses against infused cells was detected. In conclusion, adoptive immunotherapy with CD20-specific T cells was well tolerated and was associated with antitumor activity. We will pursue alternative gene transfer technologies and culture conditions in future studies to improve CAR expression and cell production efficiency.
细胞免疫反应有可能引发淋巴瘤患者显著且持久的临床缓解。最近的临床试验数据表明，嵌合抗原受体 (CAR) 修饰 T 细胞是一种很有前途的策略。含有共刺激域的 CAR 的 T 细胞对肿瘤的活性得到了改善。我们进行了一项试点临床试验，在复发的惰性 B 细胞和套细胞淋巴瘤患者中测试了一种具有 CD28 和 4-1BB 共刺激域的“第三代”CD20 特异性 CAR。招募了 4 名患者，其中 3 名在环磷酰胺淋巴耗竭后接受了 T 细胞输注。治疗耐受性良好，尽管有 1 名患者出现短暂的输注症状。2 名无可评估疾病的患者在输注后 12 个月和 24 个月时保持无进展。第 3 名患者有客观的部分缓解，在输注后 12 个月时复发。通过定量 PCR 在肿瘤部位和外周血中检测到修饰后的 T 细胞，尽管水平较低，但长达 1 年。未检测到针对输注细胞的宿主免疫反应的证据。总之，用 CD20 特异性 T 细胞进行过继免疫治疗耐受性良好，并与抗肿瘤活性相关。我们将在未来的研究中探索替代基因转移技术和培养条件，以提高 CAR 的表达和细胞生产效率。
