CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit
CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit
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DOI：
10.1073/pnas.0810114105
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发表时间：
2008-12-23
影响因子：
11.1
通讯作者：
Wolchok, Jedd D.
中科院分区：
文献类型：
--
作者：
Yuan, Jianda;Gnjatic, Sacha;Wolchok, Jedd D.
已显示阻断由细胞毒性T淋巴细胞相关抗原4（CTLA-4）介导的抑制信号可增强T细胞应答并诱导转移性黑素瘤患者的持久临床应答。抗CTLA-4治疗对人类免疫应答的功能影响仍不清楚。为了探索这一点，我们分析了用伊匹单抗（一种全人抗CTLA-4单克隆抗体）治疗的转移性黑色素瘤患者的免疫相关不良事件和免疫应答。根据免疫学监测的合适标本的可用性选择了15例患者，其中8例显示出临床获益的证据。有临床获益证据的8名患者中有5名具有NY-ESO-1抗体，而7名临床无应答者中没有一名为NY-ESO-1血清阳性。所有5名NY-ESO-1血清阳性患者在接受伊匹单抗治疗后均具有针对NY-ESO-1的明确可检测的CD 4（+）和CD 8（+）T细胞。1例NY-ESO-1血清阴性临床应答者也有NY-ESO-1 CD 4（+）和CD 8（+）T细胞应答，可能与既往接种NY-ESO-1疫苗有关。在分析的5例临床无应答者中，只有1例患者具有NY-ESO-1 CD 4（+）T细胞应答，该患者未检测到抗NY-ESO-1抗体。总体而言，在抗CTLA-4治疗期间，NY-ESO-1特异性T细胞应答的频率和功能性增加，揭示了IFN-γ、MIP-1 β和TNF-α的多功能应答模式。因此，我们认为CTLA-4阻断增强了具有持久客观临床应答和稳定疾病的患者的NY-ESO-1抗原特异性B细胞和T细胞免疫应答。这些数据为抗CTLA-4治疗的功效提供了免疫学原理，并呼吁将联合收割机NY-ESO-1疫苗接种与CTLA-4阻断相结合的免疫学设计。
Blockade of inhibitory signals mediated by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) has been shown to enhance T cell responses and induce durable clinical responses in patients with metastatic melanoma. The functional impact of anti-CTLA-4 therapy on human immune responses is still unclear. To explore this, we analyzed immune-related adverse events and immune responses in metastatic melanoma patients treated with ipilimumab, a fully human anti-CTLA-4 monoclonal antibody. Fifteen patients were selected on the basis of availability of suitable specimens for immunologic monitoring, and eight of these showed evidence of clinical benefit. Five of the eight patients with evidence of clinical benefit had NY-ESO-1 antibody, whereas none of seven clinical non-responders was seropositive for NY-ESO-1. All five NY-ESO-1 seropositive patients had clearly detectable CD4(+) and CD8(+) T cells against NY-ESO-1 following treatment with ipilimumab. One NY-ESO-1 seronegative clinical responder also had a NY-ESO-1 CD4(+) and CD8(+) T cell response, possibly related to prior vaccination with NY-ESO-1. Among five clinical non-responders analyzed, only one had a NY-ESO-1 CD4(+) T cell response and this patient did not have detectable anti-NY-ESO-1 antibody. Overall, NY-ESO-1-specific T cell responses increased in frequency and functionality during anti-CTLA-4 treatment, revealing a polyfunctional response pattern of IFN-gamma, MIP-1 beta and TNF-alpha. We therefore suggest that CTLA-4 blockade enhanced NY-ESO-1 antigen-specific B cell and T cell immune responses in patients with durable objective clinical responses and stable disease. These data provide an immunologic rationale for the efficacy of anti-CTLA-4 therapy and call for immunotherapeutic designs that combine NY-ESO-1 vaccination with CTLA-4 blockade.