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Clin Cancer Res. 2017 Aug 15;23(16):4556-4568. doi: 10.1158/1078-0432.CCR-16-2821. Epub 2017 May 3.

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.

Author information

1
Lung Cancer Research Program, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California. jaymoonlee@mednet.ucla.edu sdubinett@mednet.ucla.edu.
2
Department of Surgery, Division of Thoracic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California.
3
Lung Cancer Research Program, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California.
4
Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California.
5
Department of Medicine, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
6
Department of Radiology, David Geffen School of Medicine at UCLA, Los Angeles, California.
7
Department of Transfusion Medicine, NIH, Bethesda, Maryland.
8
Department of Dermatology, David Geffen School of Medicine at UCLA, Los Angeles, California.
9
Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, California.
10
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California.
11
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
12
Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, California.
13
Department of Biostatistics, Division of General Internal Medicine and Health Services Research, David Geffen School of Medicine at UCLA, Los Angeles, California.
14
Molecular Gene Medicine Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California.
15
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California.

Abstract

Purpose: 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.

PMID:
28468947
PMCID:
PMC5599263
DOI:
10.1158/1078-0432.CCR-16-2821
[Indexed for MEDLINE]
Free PMC Article

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