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Generation of a Novel Dendritic-cell Vaccine Using Melanoma and Squamous Cancer Stem Cells
Published on: January 6, 2014
An Anticancer Drug Cocktail of Three Kinase Inhibitors Improved Response to a Dendritic Cell-Based Cancer Vaccine
Jitao Guo1, Elena Muse1, Allison J Christians1
1Division of Medical Oncology, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
Abstract:
Monocyte-derived dendritic cell (moDC)-based cancer therapies intended to elicit antitumor T-cell responses have limited efficacy in most clinical trials. However, potent and sustained antitumor activity in a limited number of patients highlights the therapeutic potential of moDCs. In vitro culture conditions used to generate moDCs can be inconsistent, and moDCs generated in vitro are less effective than natural DCs. On the basis of our study highlighting the ability for certain kinase inhibitors to enhance tumor antigenicity, we therefore screened kinase inhibitors for their ability to improve DC immunogenicity. We identified AKT inhibitor MK2206, DNA-PK inhibitor NU7441, and MEK inhibitor trametinib as the compounds most effective at modulating moDC immunogenicity. The combination of these drugs, referred to as MKNUTRA, enhanced moDC activity over treatment with individual drugs while exhibiting minimal toxicity. An evaluation of 335 activation and T-cell-suppressive surface proteins on moDCs revealed that MKNUTRA treatment more effectively matured cells and reduced the expression of tolerogenic proteins as compared with control moDCs. MKNUTRA treatment imparted to ICT107, a glioblastoma (GBM) DC-based vaccine that has completed phase II trials, an increased ability to stimulate patient-derived autologous CD8+ T cells against the brain tumor antigens IL13Rα2(345-354) and TRP2(180-188) In vivo, treating ICT107 with MKNUTRA, prior to injection into mice with an established GBM tumor, reduced tumor growth kinetics. This response was associated with an increased frequency of tumor-reactive lymphocytes within tumors and in peripheral tissues. These studies broaden the application of targeted anticancer drugs and highlight their ability to increase moDC immunogenicity.
Insights
Kinase inhibitors MK2206, NU7441, and trametinib, combined as MKNUTRA, enhance dendritic cell (DC) immunogenicity. This combination therapy improved DC-based glioblastoma vaccine efficacy in preclinical models, reducing tumor growth and increasing tumor-reactive T cells.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Monocyte-derived dendritic cell (moDC)-based cancer therapies show promise but have limited clinical efficacy.
- In vitro generation of moDCs can be inconsistent, leading to reduced effectiveness compared to natural DCs.
- Targeted kinase inhibitors have potential to enhance tumor antigenicity and DC immunogenicity.
Purpose of the Study:
- To screen kinase inhibitors for their ability to improve moDC immunogenicity.
- To evaluate the efficacy of a combination of identified kinase inhibitors (MKNUTRA) in enhancing moDC function and anti-glioblastoma activity.
Main Methods:
- Screening of kinase inhibitors, including AKT inhibitor MK2206, DNA-PK inhibitor NU7441, and MEK inhibitor trametinib.
- Combination treatment (MKNUTRA) of moDCs and evaluation of surface protein expression.
- Assessment of MKNUTRA-treated ICT107 vaccine's ability to stimulate CD8+ T cells against glioblastoma antigens.
- In vivo studies using a murine glioblastoma model to assess tumor growth kinetics and immune cell infiltration.
Main Results:
- MK2206, NU7441, and trametinib were identified as effective modulators of moDC immunogenicity.
- The MKNUTRA combination enhanced moDC activity more than individual drugs with minimal toxicity.
- MKNUTRA treatment promoted moDC maturation and reduced tolerogenic protein expression.
- MKNUTRA-enhanced ICT107 vaccine increased CD8+ T cell stimulation against glioblastoma antigens.
- In vivo, MKNUTRA-treated ICT107 reduced glioblastoma tumor growth and increased tumor-reactive lymphocytes.
Conclusions:
- Targeted kinase inhibitors, particularly the MKNUTRA combination, can significantly enhance moDC immunogenicity.
- MKNUTRA represents a promising strategy to improve the efficacy of DC-based cancer vaccines, including for glioblastoma.
- This approach broadens the application of targeted anticancer drugs in immunotherapy.
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