Phase I Trial of Intratumoral Injection of CCL21 Gene-Modified Dendritic Cells in Lung Cancer Elicits Tumor-Specific Immune Responses and CD8(+) T-cell Infiltration.
Phase I Trial of Intratumoral Injection of CCL21 Gene-Modified Dendritic Cells in Lung Cancer Elicits Tumor-Specific Immune Responses and CD8(+) T-cell Infiltration.
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DOI：
10.1158/1078-0432.ccr-16-2821
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发表时间：
2017-08-15
期刊：
影响因子：
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通讯作者：
Dubinett SM
中科院分区：
文献类型：
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作者：
Lee JM;Lee MH;Garon E;Goldman JW;Salehi-Rad R;Baratelli FE;Schaue D;Wang G;Rosen F;Yanagawa J;Walser TC;Lin Y;Park SJ;Adams S;Marincola FM;Tumeh PC;Abtin F;Suh R;Reckamp KL;Lee G;Wallace WD;Lee S;Zeng G;Elashoff DA;Sharma S;Dubinett SM
进行了一项I期研究，以确定晚期非小细胞肺癌（NSCLC）患者瘤内（IT）给予表达CCL 21基因的腺病毒（Ad）载体转导的自体树突状细胞（DC）（Ad-CCL 21-DC）后的安全性、临床疗效和抗肿瘤免疫应答。我们评估了原位疫苗接种后的安全性和肿瘤抗原特异性免疫应答（ClinicalTrials.gov：NCT 01574222）。16例IIIB/IV期NSCLC受试者通过CT或支气管镜引导的IT注射（第0天和第7天）接受了两次疫苗接种（1 × 106、5 × 106、1 × 107或3 × 107个树突状细胞/注射）。在ELISPOT测定中通过肿瘤抗原特异性外周血淋巴细胞诱导IFN-γ来评估免疫应答。通过免疫组织化学（IHC）评价肿瘤活检的CD 8 + T细胞，并通过IHC和实时PCR（RT-PCR）评价PD-L1表达。25%（4/16）的患者在第56天病情稳定。中位生存期为3.9个月。ELISPOT检测显示16例患者中有6例对肿瘤相关抗原（TAA）有全身反应。在54%的受试者中诱导肿瘤CD 8 + T细胞浸润（7/13;每mm 2的CD 8 + T细胞数量平均增加3.4倍）。接种疫苗后CD 8 + T细胞增加的患者显示PD-L1 mRNA表达显著增加。肿瘤内接种Ad-CCL 21-DC导致1）诱导全身肿瘤抗原特异性免疫应答，2）增强肿瘤CD 8 + T细胞浸润，3）增加肿瘤PD-L1表达。未来的研究将评估PD-1/PD-L1检查点抑制联合DC-CCL 21原位疫苗接种的联合治疗的作用。
A phase I study was conducted to determine safety, clinical efficacy, and anti-tumor immune responses in patients with advanced non-small cell lung carcinoma (NSCLC) following intratumoral (IT) administration of autologous dendritic cells (DC) transduced with an adenoviral (Ad) vector expressing the CCL21 gene (Ad-CCL21-DC). We evaluated safety and tumor antigen-specific immune responses following in situ vaccination (ClinicalTrials.gov: NCT01574222). Sixteen stage IIIB/IV NSCLC subjects received two vaccinations (1 × 106, 5 × 106, 1 × 107, or 3 × 107 dendritic cells/injection) by CT- or bronchoscopic-guided IT injections (days 0 and 7). Immune responses were assessed by tumor antigen-specific peripheral blood lymphocyte induction of IFN-γ in ELISPOT assays. Tumor biopsies were evaluated for CD8+ T cells by immunohistochemistry (IHC) and for PD-L1 expression by IHC and real-time PCR (RT-PCR). Twenty-five percent (4/16) of patients had stable disease at day 56. Median survival was 3.9 months. ELISPOT assays revealed 6 of 16 patients had systemic responses against tumor associated antigens (TAA). Tumor CD8+ T cell infiltration was induced in 54% of subjects (7/13; 3.4-fold average increase in the number of CD8+ T cells per mm2). Patients with increased CD8+ T cells following vaccination showed significantly increased PD-L1 mRNA expression. Intratumoral vaccination with Ad-CCL21-DC resulted in 1) induction of systemic tumor antigen-specific immune responses, 2) enhanced tumor CD8+ T cell infiltration, and 3) increased tumor PD-L1 expression. Future studies will evaluate the role of combination therapies with PD-1/PD-L1 checkpoint inhibition combined with DC-CCL21 in situ vaccination.