Comparative Study

. 2014 Sep;151(3):447-53.

doi: 10.1177/0194599814533775. Epub 2014 May 13.

A cytokine-delivering polymer is effective in reducing tumor burden in a head and neck squamous cell carcinoma murine model

Affiliations

¹ Department of Head and Neck Surgery, University of California, Los Angeles, Los Angeles, California, USA UCLA Head and Neck Cancer Program, University of California, Los Angeles, Los Angeles, California, USA Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
² Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA.
³ Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA Veterans' Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA.
⁴ Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California, USA.
⁵ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA Department of Biostatistics, University of California, Los Angeles, Los Angeles, California, USA.
⁶ Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA Veterans' Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA.
⁷ Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA Division of Advanced Prosthodontics, Biomaterials, and Hospital Dentistry, University of California, Los Angeles, Los Angeles, California, USA Department of Materials Science and Engineering, University of California, Los Angeles, Los Angeles, California, USA Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
⁸ Department of Head and Neck Surgery, University of California, Los Angeles, Los Angeles, California, USA UCLA Head and Neck Cancer Program, University of California, Los Angeles, Los Angeles, California, USA Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA mstjohn@mednet.ucla.edu.

PMID: 24825873
PMCID: PMC4167678
DOI: 10.1177/0194599814533775

Comparative Study

A cytokine-delivering polymer is effective in reducing tumor burden in a head and neck squamous cell carcinoma murine model

Yuan Lin et al. Otolaryngol Head Neck Surg. 2014 Sep.

. 2014 Sep;151(3):447-53.

doi: 10.1177/0194599814533775. Epub 2014 May 13.

Authors

Affiliations

¹ Department of Head and Neck Surgery, University of California, Los Angeles, Los Angeles, California, USA UCLA Head and Neck Cancer Program, University of California, Los Angeles, Los Angeles, California, USA Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
² Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA.
³ Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA Veterans' Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA.
⁴ Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California, USA.
⁵ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA Department of Biostatistics, University of California, Los Angeles, Los Angeles, California, USA.
⁶ Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA Veterans' Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA.
⁷ Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA Division of Advanced Prosthodontics, Biomaterials, and Hospital Dentistry, University of California, Los Angeles, Los Angeles, California, USA Department of Materials Science and Engineering, University of California, Los Angeles, Los Angeles, California, USA Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
⁸ Department of Head and Neck Surgery, University of California, Los Angeles, Los Angeles, California, USA UCLA Head and Neck Cancer Program, University of California, Los Angeles, Los Angeles, California, USA Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA mstjohn@mednet.ucla.edu.

PMID: 24825873
PMCID: PMC4167678
DOI: 10.1177/0194599814533775

Abstract

Objective: This study aimed to evaluate the therapeutic efficacy of a novel polymer platform delivering cisplatin and cytokines in the treatment of head and neck squamous cell carcinoma (HNSCC).

Study design: In vivo study.

Setting: Academic research laboratory.

Subjects and methods: Mice were randomized to receive implantation of (1) no polymer, (2) plain polymer, (3) plain polymer with local cisplatin injection, or (4) cisplatin polymer. The 2 groups of mice implanted with cisplatin polymer or no polymer were further randomized to receive (1) 4 Grays external beam radiation for 4 days or (2) no radiation. For cytokine studies, mice were grouped into (1) no polymer, (2) plain polymer, (3) plain polymer with intratumoral injection of recombinant CCL21 twice a week, (4) polymer containing parental dendritic cells, or (5) polymer containing dendritic cells secreting CCL21 (DC-CCL21).

Results: The cisplatin-secreting polymer effectively reduced tumors in the mice by more than 16-fold (P < .01). We also observed a statistically significant lower tumor weight among mice treated with cisplatin polymer and concomitant radiation compared to control groups. The DC-CCL21 polymer reduced SCCVII/SF tumors in the C3H/HeJ mice by more than 41% (P < .01).

Conclusion: Herein, we demonstrate the efficacy of a novel polymer platform in delivering cisplatin and cytokines. We also demonstrate that we can effectively grow dendritic cells in the polymer that can actively secrete CCL21 for a minimum of 5 days. This polymer may represent a new therapeutic modality for patients with HNSCC. Once this polymer platform is optimized, we will plan to pursue prospective trials in patients with HNSCC.

Keywords: head and neck cancer; novel therapeutics; polymer; squamous cell carcinoma.

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Figures

**Figure 1. Cisplatin Polymer Effectively Reduces the Growth of Mouse SCCVII/SF**
4×10⁵ SCVII/SF tumor cells were inoculated in C3H mice. The implanted cisplatin polymer significantly reduced tumor growth by 16 fold compared to controls. n=8 mice/group,** p<0.01 compared to surgery only.

**Figure 2. Time-series Plot of Tumor Size in the Four Treatment Arms**
The effects of treatments were assessed with a repeated measures ANOVA model. Treatment with cisplatin polymer and radiation resulted in significantly reduced tumor size over time (p=0.03 and 0.001, respectively).

**Figure 3. DC-CCL21 cultured in the polymer is capable to producing CCL21 in vitro**
(A) DC-CCL21 were grown directly on plates or in polymer at different initial densities as indicated. Growth curve were made using cell numbers courted five days later (open bar). (B) Time dependent continuous release of CCL21 from DC-CCL21 in polymer. (C) Density dependent release of CCL21 from DC-CCL21 in polymer.

**Figure 4. Polymer-based DC-CCL21 treatment inhibits tumor growth in a partially resected HNSCC model**
Established SCCVII/SF tumors were partially resected and were treated with control, polymer, polymer+CCL21 injection, polymer+DC and polymer+DC-CCL21. Polymer+DC-CCL21 treatment exhibited a significant antitumor effect, starting from day 6 to day 12 (p<0.05). In contrast, polymer with CCL21 injection only demonstrated a weak and insignificant decrease in tumor growth, compared to control group or plain polymer group (p>0.05). Plain polymer or polymer+DC treatment showed no significant difference in tumor volume compared to the control group (p>0.05). Results are representative of three independent experiments; bar, ±SD.

**Figure 5. DC-CCL21 polymer recruits dendritic cells and T cells and inhibits regulatory T cells in vivo**
Flow cytometry was performed to evaluate single cell suspensions of tumor nodules. Animals receiving DC-CCL21 polymer therapy exhibited a significant increase in the frequency of CD4+ T cell and CD11c+ dendritic cells, as well as a marked decrease in CD4+CD25+ regulatory T cells infiltrating the tumor site.

**Figure 6. DC-CCL21 treatment inhibits EMT in squamous cell tumors**
Epithelial markers, including E-cadherin, beta-catenin and gamma-catenin, are increased, whereas the mesenchymal marker vimentin is decreased in the tumors from the DC-CCL21 polymer treatment group, as compared to tumors from the plain polymer control group.

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A cytokine-delivering polymer is effective in reducing tumor burden in a head and neck squamous cell carcinoma murine model

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A cytokine-delivering polymer is effective in reducing tumor burden in a head and neck squamous cell carcinoma murine model

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