CD8+ enriched "young" tumor infiltrating lymphocytes can mediate regression of metastatic melanoma.
CD8+ enriched "young" tumor infiltrating lymphocytes can mediate regression of metastatic melanoma.
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DOI：
10.1158/1078-0432.ccr-10-1297
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发表时间：
2010-12-15
期刊：
影响因子：
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通讯作者：
Rosenberg SA
中科院分区：
文献类型：
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作者：
Dudley ME;Gross CA;Langhan MM;Garcia MR;Sherry RM;Yang JC;Phan GQ;Kammula US;Hughes MS;Citrin DE;Restifo NP;Wunderlich JR;Prieto PA;Hong JJ;Langan RC;Zlott DA;Morton KE;White DE;Laurencot CM;Rosenberg SA
肿瘤浸润淋巴细胞（TIL）和白细胞介素(IL)-2在淋巴细胞耗损后给予，可导致对批准的治疗难治的大块转移性黑色素瘤的持久完全消退。然而，为每个患者产生独特的肿瘤反应性TIL培养可能非常困难。因此，我们研究了未筛选的CD8+富集的“年轻”TIL的临床和免疫学影响。开发了生成TIL的方法，使培养时间最小化，并消除了个体化肿瘤反应性筛选步骤。33例患者在非清髓性淋巴细胞清除（NMA）后接受了这些CD8+富集的年轻TIL和IL-2治疗。另外23例患者在NMA和6Gy的全身照射（TBI）下进行淋巴清除后，接受CD8+富集的年轻TIL和IL-2治疗。在122例连续黑色素瘤患者中，83%的患者成功建立了用于治疗的年轻TIL培养物。接受CD8+富集的年轻TIL和NMA治疗的33例患者中有19例（58%）有客观缓解（RECIST），包括3例完全缓解。接受TIL和6Gy TBI治疗的23例患者中有11例（48%）客观缓解，包括2例完全缓解。TIL输注1个月后，外周血CD8+细胞绝对数量与应答高度相关。这项研究表明，一种快速和简化的方法可以可靠地生成富含CD8+的年轻TIL，作为晚期黑色素瘤的个体化治疗，并可能使这种潜在的有效治疗应用于其他机构，并覆盖更多的患者。
Tumor infiltrating lymphocytes (TIL) and interleukin (IL)-2 administered following lymphodepletion can cause the durable complete regression of bulky metastatic melanoma in patients refractory to approved treatments. However, the generation of a unique tumor-reactive TIL culture for each patient may be prohibitively difficult. We therefore investigated the clinical and immunological impact of unscreened, CD8+ enriched “young” TIL. Methods were developed for generating TIL that minimized the time in culture and eliminated the individualized tumor-reactivity screening step. Thirty-three patients were treated with these CD8+ enriched young TIL and IL-2 following non-myeloablative lymphodepletion (NMA). Twenty-three additional patients were treated with CD8+ enriched young TIL and IL-2 after lymphodepletion with NMA and 6Gy of total body irradiation (TBI). Young TIL cultures for therapy were successfully established from 83% of 122 consecutive melanoma patients. Nineteen of 33 patients (58%) treated with CD8+ enriched young TIL and NMA had an objective response (RECIST) including three complete responders. Eleven of 23 patients (48%) treated with TIL and 6Gy TBI had an objective response including two complete responders. At one month after TIL infusion the absolute CD8+ cell numbers in the periphery were highly correlated with response. This study shows that a rapid and simplified method can be used to reliably generate CD8+ enriched young TIL for administration as an individualized therapy for advanced melanoma, and may allow this potentially effective treatment to be applied at other institutions and to reach additional patients.