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Preparation of Tumor Antigen-loaded Mature Dendritic Cells for Immunotherapy
Published on: August 1, 2013
Characteristics of a CCL21 Gene-Modified Dendritic Cell Vaccine Utilized for a Clinical Trial in Non-Small Cell Lung
Michael S Oh1, Camelia Dumitras1, Ramin Salehi-Rad1,2,3
1Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
Abstract:
The treatment of non-small cell lung cancer has made major strides with the use of immune checkpoint inhibitors; however, there remains a significant need for therapies that can overcome immunotherapy resistance. Dendritic cell (DC) vaccines have been proposed as a therapy that can potentially enhance the antitumor immune response. We have embarked on a phase I clinical trial of a vaccine consisting of monocyte-derived DCs (moDC) modified to express the chemokine C-C motif chemokine ligand 21 (CCL21-DC) given in combination with pembrolizumab. In this study, we report a comprehensive characterization of this CCL21-DC vaccine and interrogate the effects of multiple factors in the manufacturing process. We show that the cellular makeup of the CCL21-DC vaccine is heterogeneous because of the presence of passenger lymphocytes at a proportion that is highly variable among patients. Single-cell RNA sequencing of vaccines revealed further heterogeneity within the moDC compartment, with cells spanning a spectrum of DC phenotypes. Transduction with a CCL21-containing adenoviral vector augmented CCL21 secretion by moDCs, but otherwise had a minimal effect on vaccine characteristics. A single freeze-thaw cycle for stored vaccines was associated with minor alterations to the DC phenotype, as was the use of healthy donors rather than patient autologous blood. Our results highlight important considerations for the production of DC vaccines and identify underexplored factors that may affect their efficacy and immunologic impact.
Insights
This study characterizes a dendritic cell (DC) vaccine combined with pembrolizumab for non-small cell lung cancer. Manufacturing factors like donor source and storage impact vaccine consistency, highlighting production considerations.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Immune checkpoint inhibitors have advanced non-small cell lung cancer (NSCLC) treatment.
- Therapies are needed to overcome immunotherapy resistance in NSCLC.
- Dendritic cell (DC) vaccines show potential to enhance antitumor immune responses.
Purpose of the Study:
- To characterize a novel monocyte-derived DC (moDC) vaccine engineered to express chemokine C-C motif chemokine ligand 21 (CCL21-DC).
- To evaluate the combination of CCL21-DC vaccine with pembrolizumab in a phase I clinical trial.
- To investigate the impact of manufacturing process variables on CCL21-DC vaccine characteristics.
Main Methods:
- Phase I clinical trial of CCL21-DC vaccine combined with pembrolizumab.
- Comprehensive characterization of the CCL21-DC vaccine product.
- Single-cell RNA sequencing to analyze moDC heterogeneity.
- Assessment of manufacturing factors including donor source and cryopreservation.
Main Results:
- CCL21-DC vaccines exhibited significant cellular heterogeneity due to variable passenger lymphocyte presence.
- Single-cell RNA sequencing revealed a spectrum of moDC phenotypes within vaccines.
- CCL21 transduction enhanced CCL21 secretion but minimally altered other vaccine characteristics.
- Cryopreservation and use of healthy donor cells caused minor alterations in DC phenotype.
Conclusions:
- Manufacturing processes for DC vaccines require careful consideration to ensure consistency.
- Factors such as donor variability and cryopreservation can influence DC vaccine immunologic impact.
- Further research is needed to optimize DC vaccine production for enhanced efficacy in cancer immunotherapy.
