Phase I Trial of Intratumoral Injection ofCCL21Gene–Modified Dendritic Cells in Lung Cancer Elicits Tumor-Specific Immune Responses and CD8+ T-cell Infiltration

1区 · 医学

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作者: Wang, Gerald ; Zeng, Gang ; Walser, Tonya C. ; Reckamp, Karen L. ; Suh, Robert ; Goldman, Jonathan W. ; Schaue, Dörthe ; Lin, Ying ; Adams, Sharon ; Dubinett, Steven M. ; Park, Stacy J. ; Sharma, Sherven ; Yanagawa, Jane ; Baratelli, Felicita E. ; Lee, Mi-Heon ; Lee, Jay M. ; Tumeh, Paul C. ; Rosen, Fran ; Wallace, William D. ; Garon, Edward ; Lee, Sarah ; Lee, Gina ; Salehi-Rad, Ramin ; Abtin, Fereidoun ; Marincola, Francesco M. ; Elashoff, David A.

AbstractPurpose: A phase I study was conducted to determine safety, clinical efficacy, and antitumor immune responses in patients with advanced non–small cell lung carcinoma (NSCLC) following intratumoral 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).Experimental Design: Sixteen stage IIIB/IV NSCLC subjects received two vaccinations (1 × 106, 5 × 106, 1 × 107, or 3 × 107 DCs/injection) by CT- or bronchoscopic-guided intratumoral injections (days 0 and 7). Immune responses were assessed by tumor antigen–specific peripheral blood lymphocyte induction of IFNγ in ELISPOT assays. Tumor biopsies were evaluated for CD8+ T cells by IHC and for PD-L1 expression by IHC and real-time PCR (RT-PCR).Results: 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.Conclusions: Intratumoral vaccination with Ad-CCL21-DC resulted in (i) induction of systemic tumor antigen–specific immune responses; (ii) enhanced tumor CD8+ T-cell infiltration; and (iii) 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. Clin Cancer Res; 23(16); 4556–68. ©2017 AACR.

2006-03-15·Cancer Research1区 · 医学

Intrapulmonary Administration of CCL21 Gene-Modified Dendritic Cells Reduces Tumor Burden in Spontaneous Murine Bronchoalveolar Cell Carcinoma

1区 · 医学

Article

作者: Strieter, Robert M. ; Hillinger, Sven ; Yang, Seok-Chul ; Dubinett, Steven M. ; Sharma, Sherven ; Batra, Raj K. ; Reckamp, Karen L.

AbstractThe antitumor efficiency of dendritic cells transduced with an adenovirus vector expressing secondary lymphoid chemokine (CCL21) was evaluated in a murine model of spontaneous bronchoalveolar cell carcinoma. The transgenic mice (CC-10 TAg) express the SV40 large T antigen (TAg) under the Clara cell promoter, develop bilateral, multifocal, and pulmonary adenocarcinomas, and die at 4 months as a result of progressive pulmonary tumor burden. A single intratracheal administration of CCL21 gene-modified dendritic cells (DC-AdCCL21) led to a marked reduction in tumor burden with extensive mononuclear cell infiltration of the tumors. The reduction in tumor burden was accompanied by the enhanced elaboration of type 1 cytokines [IFN-γ, interleukin (IL)-12, and granulocyte macrophage colony-stimulating factor] and antiangiogenic chemokines (CXCL9 and CXCL10) but a concomitant decrease in the immunosuppressive molecules (IL-10, transforming growth factor-β, prostaglandin E2) in the tumor microenvironment. The DC-AdCCL21 therapy group revealed a significantly greater frequency of tumor-specific T cells releasing IFN-γ compared with the controls. Continuous therapy with weekly intranasal delivery of DC-AdCCL21 significantly prolonged median survival by >7 weeks in CC-10 TAg mice. Both innate natural killer and specific T-cell antitumor responses significantly increased following DC-AdCCL21 therapy. Significant reduction in tumor burden in a model in which tumors develop in an organ-specific manner provides a strong rationale for further evaluation of intrapulmonary-administered DC-AdCCL21 in regulation of tumor immunity and genetic immunotherapy for lung cancer.(Cancer Res 2006; 66(6): 3205-13)

2004-04-15·Clinical Cancer Research1区 · 医学

Intratumoral Administration of Dendritic Cells Overexpressing CCL21 Generates Systemic Antitumor Responses and Confers Tumor Immunity

1区 · 医学

Article

作者: Huang, Min ; Zhu, Li ; Sharma, Sherven ; Gardner, Brian ; Strieter, Robert M. ; Atianzar, Kimberly ; Kuo, Brian Y. ; Yang, Seok-Chul ; Batra, Raj K. ; Hillinger, Sven ; Dubinett, Steven M. ; Zhang, Ling ; Riedl, Karen

AbstractTo achieve in situ tumor antigen uptake and presentation, intratumoral administration of ex vivo-generated, gene-modified murine bone marrow-derived dendritic cells (DC) was used in a murine lung cancer model. To attract mature host DC and activated T cells at the tumor site, the DC were transduced with an adenoviral vector expressing secondary lymphoid tissue chemokine (CCL21/SLC). Sixty percent of the mice treated with 106 DC-AdCCL21 intratumorally (7–10 ng/ml/106 cells/24 h of CCL21) at weekly intervals for 3 weeks showed complete tumor eradication, whereas only 25% of mice had complete resolution of tumors when mice were treated with fibroblasts expressing CCL21. In contrast only 12% of the mice treated with unmodified or control vector modified DC (DC-AdCV) showed complete tumor eradication. DC-AdCCL21 administration led to increases in the CD4+, CD8+, and CD3+CXCR3+ T cells, as well as DC expressing CD11c+ DEC205+. CD4+CD25+ T-regulatory cells infiltrating the tumors were markedly reduced after DC-AdCCL21 therapy. The tumor site cellular infiltrates were accompanied by the enhanced elaboration of granulocyte macrophage colony-stimulating factor, IFN-γ, MIG/CXCL9, IP-10/CXCL10, and interleukin 12, but decreases in the immunosuppressive mediators transforming growth factor β and prostaglandin E2. DC-AdCCL21-treated tumor-bearing mice showed enhanced frequency of tumor-specific T lymphocytes secreting IFN-γ, and tumor protective immunity was induced after DC-AdCCL21 therapy. In vivo depletion of IP-10/CXCL10, MIG/CXCL9, or IFN-γ significantly reduced the antitumor efficacy of DC-AdCCL21. These findings provide a strong rationale for the evaluation of DC-AdCCL21 in cancer immunotherapy.

100 项与 DC-Ad-CCL-21 intratumoral therapy(U.S. Department of Veteran Affairs) 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
肺癌	临床1期	-	University of California, Los Angeles	-
肺癌	临床1期	-	US Department of Veterans Affairs (District of Columbia)	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


WCLC2016	N/A	-	16	Ad-CCL21-DC	(糧壓鏇遞顧廠鏇鹽願鹹) = 齋鬱廠壓範蓋膚遞壓築廠築觸繭顧構築鑰鹽觸 (積鬱憲遞餘構獵鹽憲鏇 ) 更多	-	2016-12-06