Phase I Trial of Intratumoral Injection of <i>CCL21</i> Gene-Modified Dendritic Cells in Lung Cancer Elicits Tumor-Specific Immune Responses and CD8<sup>+</sup> T-cell Infiltration.
Abstract
<b>Purpose:</b> 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 <i>CCL21</i> gene (Ad-CCL21-DC). We evaluated safety and tumor antigen-specific immune responses following <i>in situ</i> vaccination (ClinicalTrials.gov: NCT01574222).<b>Experimental Design:</b> Sixteen stage IIIB/IV NSCLC subjects received two vaccinations (1 × 10<sup>6</sup>, 5 × 10<sup>6</sup>, 1 × 10<sup>7</sup>, or 3 × 10<sup>7</sup> 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<sup>+</sup> T cells by IHC and for PD-L1 expression by IHC and real-time PCR (RT-PCR).<b>Results:</b> 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<sup>+</sup> T-cell infiltration was induced in 54% of subjects (7/13; 3.4-fold average increase in the number of CD8<sup>+</sup> T cells per mm<sup>2</sup>). Patients with increased CD8<sup>+</sup> T cells following vaccination showed significantly increased PD-L1 mRNA expression.<b>Conclusions:</b> Intratumoral vaccination with Ad-CCL21-DC resulted in (i) induction of systemic tumor antigen-specific immune responses; (ii) enhanced tumor CD8<sup>+</sup> 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 <i>in situ</i> vaccination. <i>Clin Cancer Res; 23(16); 4556-68. ©2017 AACR</i>.
EDRN PI Authors
Medline Author List
- Abtin F
- Adams S
- Baratelli FE
- Dubinett SM
- Elashoff DA
- Garon E
- Goldman JW
- Lee G
- Lee JM
- Lee MH
- Lee S
- Lin Y
- Marincola FM
- Park SJ
- Reckamp KL
- Rosen F
- Salehi-Rad R
- Schaue D
- Sharma S
- Suh R
- Tumeh PC
- Wallace WD
- Walser TC
- Wang G
- Yanagawa J
- Zeng G