Determinants of successful CD8+ T-cell adoptive immunotherapy for large established tumors in mice.
Determinants of successful CD8+ T-cell adoptive immunotherapy for large established tumors in mice.
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DOI：
10.1158/1078-0432.ccr-11-0503
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发表时间：
2011-08-15
期刊：
影响因子：
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通讯作者：
Restifo NP
中科院分区：
文献类型：
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作者：
Klebanoff CA;Gattinoni L;Palmer DC;Muranski P;Ji Y;Hinrichs CS;Borman ZA;Kerkar SP;Scott CD;Finkelstein SE;Rosenberg SA;Restifo NP
肿瘤浸润或基因工程 T 细胞的过继细胞转移 (ACT) 可以在转移性癌症患者中引起持久的反应。该疗法可包含多个临床可修改参数，包括细胞剂量和表型、体内抗原再刺激和常见的伽马链 (γc) 细胞因子支持。然而，这些单独成分对抗肿瘤反应强度的相对贡献尚未量化。为了系统、定量地评估每个变量，我们采用了 Pmel-1 小鼠模型来治疗大型 B16 黑色素瘤。除了体内抗原再刺激的细胞剂量和强度之外，我们还评估了中枢记忆（TCM）、效应记忆（TEM）和干细胞记忆（TSCM）子集对肿瘤消退强度的相对功效以及临床可用的γc细胞因子（包括IL-2、IL-7、IL-15和IL-21）的剂量和类型。我们发现细胞剂量、T 细胞分化状态和病毒疫苗滴度均与肿瘤消退的程度密切相关。令人惊讶的是，尽管IL-2剂量总数与肿瘤消退相关，但没有观察到长期（≥6剂量）给药的显着益处。此外，γc细胞因子的具体类型和剂量与反应仅中度相关。总的来说，这些发现阐明了 ACT 免疫疗法成功治疗小鼠癌症的一些关键决定因素，并进一步证明 γc 细胞因子具有类似的能力，可有效驱动体内抗肿瘤 T 细胞功能。
Adoptive cell transfer (ACT) of tumor-infiltrating or genetically engineered T cells can cause durable responses in patients with metastatic cancer. Multiple clinically-modifiable parameters can comprise this therapy, including cell dose and phenotype, in vivo antigen re-stimulation, and common gamma-chain (γc) cytokine support. However, the relative contributions of each these individual components to the magnitude of the anti-tumor response have yet to be quantified. To systematically and quantitatively appraise each of these variables, we employed the Pmel-1 mouse model treating large, established B16 melanoma tumors. In addition to cell dose and magnitude of in vivo antigen re-stimulation, we also evaluated the relative efficacy of central memory (TCM), effector memory (TEM), and stem cell memory (TSCM) subsets on the strength of tumor regression as well as the dose and type of clinically available γc cytokines, including IL-2, IL-7, IL-15, and IL-21. We found that cell dose, T cell differentiation status, and viral vaccine titer each were correlated strongly and significantly with the magnitude of tumor regression. Surprisingly, although the total number of IL-2 doses was correlated with tumor regression, no significant benefit to prolonged (≥6 doses) administration was observed. Moreover, the specific type and dose of γc cytokine only moderately correlated with response. Collectively, these findings elucidate some of the key determinants of successful ACT immunotherapy for the treatment of cancer in mice and further demonstrate that γc cytokines offer a similar ability to effectively drive anti-tumor T cell function in vivo.