Three agonist antibodies in combination with high-dose IL-2 eradicate orthotopic kidney cancer in mice

Jennifer A Westwood,Phillip K Darcy,Preethi Mayura Guru,Sally M Amos,Hollie J Pegram,Janelle Sharkey,Mark J Smyth,Michael H Kershaw

doi:10.1186/1479-5876-8-42

Abstract

BackgroundCombination immunotherapies can be effective against subcutaneous tumors in mice but the effect against orthotopic malignant disease is less well characterized. In particular, a combination of three agonist antibodies, termed Tri-mAb, consisting of anti-DR5, anti-CD40 and anti-CD137 has previously been demonstrated to eradicate a large proportion of subcutaneous renal cell carcinoma (Renca) tumors (75% long-term survival), but the effect against orthotopic disease is not known.PurposeTo determine the relative response of orthotopic tumors, we inoculated Renca into the kidney followed by treatment with Tri-mAb.ResultsWe found that orthotopic tumors responded much less to treatment (~13% survival), but a significant improvement in survival was achieved through the addition of IL-2 to the treatment regimen (55% survival). All three agonist antibodies and high dose IL-2, 100,000 IU for up to six doses, were required. CD8+ T cells were also required for optimal anti-tumor responses. Coadministration of IL-2 led to enhanced T cell activity as demonstrated by an increased frequency of IFN-gamma-producing T cells in tumor-draining lymph nodes, which may have contributed to the observed improvement of therapy against kidney tumors.ImplicationsResponses of subcutaneous tumors to immunotherapy do not necessarily reflect how orthotopic tumors respond. The use of combination immunotherapy stimulating multiple facets of immunity and including cytokine support for T cells can induce effective anti-tumor responses against orthotopic and metastatic tumors.

Highlights

Immunotherapies involving combinations of various immunomodulating agents are demonstrating considerable promise for the treatment of cancer
Monoclonal antibodies targeting death receptors expressed on a range of transformed cells [1] can mediate apoptosis of a proportion of tumor cells leading to induction of tumor-specific T cells and inhibition of tumor growth in preclinical mouse models[2]
Since tumor growth and responses can vary depending on size and anatomical location, and established orthotopic metastatic cancer is considered more difficult to treat than subcutaneous disease, in the current study we sought to determine the effect of Tri-Monoclonal antibodies (mAb) against established orthotopic and metastatic renal cell carcinoma without nephrectomy and ascertain if treatment could be optimized using cytokine support

Summary

Introduction

Immunotherapies involving combinations of various immunomodulating agents are demonstrating considerable promise for the treatment of cancer. Monoclonal antibodies (mAb) targeting death receptors expressed on a range of transformed cells [1] can mediate apoptosis of a proportion of tumor cells leading to induction of tumor-specific T cells and inhibition of tumor growth in preclinical mouse models[2]. An agonistic antibody targeting CD40 expressed on antigen presenting cells has been demonstrated to lead to activation of APCs and the generation of CTL and eradication of lymphoma in mice[3]. Combination immunotherapies can be effective against subcutaneous tumors in mice but the effect against orthotopic malignant disease is less well characterized. A combination of three agonist antibodies, termed Tri-mAb, consisting of anti-DR5, anti-CD40 and anti-CD137 has previously been demonstrated to eradicate a large proportion of subcutaneous renal cell carcinoma (Renca) tumors (75% long-term survival), but the effect against orthotopic disease is not known.

Methods

Results

Conclusion