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Poxvirus-based active immunotherapy synergizes with immune checkpoint inhibitors to cause tumor regression and extend survival in preclinical models of cancer

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Journal for ImmunoTherapy of Cancer20142(Suppl 3):P124

https://doi.org/10.1186/2051-1426-2-S3-P124

Published: 6 November 2014

Keywords

  • Ipilimumab
  • Immune Checkpoint
  • Cell Immune Response
  • Immune Checkpoint Inhibitor
  • Dose Escalation Trial

Combining poxvirus-based immunotherapies which "step on the gas" to activate tumor antigen-specific T cell immune responses with immune checkpoint inhibitors (ICIs) which "release the brakes" on the immune system is a promising direction for enhancing cancer immunotherapy. Evidence for the potential clinical benefit from combination immunotherapy was obtained in a Phase I dose escalation trial. Cohorts of prostate cancer (mCRPC) patients were treated with a fixed dose of PROSTVAC, a poxvirus-based active immunotherapy, plus escalating doses of Ipilimumab, an anti-CTLA-4 ICI. The median overall survival (mOS) of 31.6 months [1] from the combined cohorts was notably longer than the mOS of mCRPC patients from an independent randomized Phase II study (PROSTVAC alone 25.1 months versus placebo 16.6 months; the most pronounced survival benefit (8.5 months) in mCRPC to date) [2]. This potentially synergistic combination of PROSTVAC and Ipilimumab warrants further exploration.

We modeled the benefit of combining poxvirus-based immunotherapy with CTLA-4 blockade using MVA-BN-HER2, which is being developed for breast cancer. In preclinical studies a dramatic increase in mOS was observed in a therapeutic CT26-HER2 lung metastasis model when mice were treated with MVA-BN-HER2 plus CTLA-4 blockade compared to either treatment alone. The improved survival with the combination therapy was accompanied by a striking increase in the magnitude and functional quality of tumor infiltrating HER-2 specific CD8 T cells [3].

Additional ICIs are identified in our preclinical studies as promising candidates for combining with poxvirus-based immunotherapies. Immune checkpoint protein expression is normally induced on activated T cells to regulate activity, and we found that MVA-BN-HER2 treatment resulted in activated CD8 T cells and elevated expression of PD-1, TIM-3, or ICOS. However, immune checkpoint proteins are chronically elevated on exhausted T cells in an immunosuppressive tumor microenvironment. In untreated tumor-bearing mice, a potentially exhausted T cell phenotype was found on CD4 and CD8 T cells characterized by increased expression or co-expression of PD-1, TIM-3, and LAG-3. We compared treatment of MVA-BN-HER2 alone or in combination with ICI antibodies against these immune checkpoint molecules in solid or metastatic CT26-HER2 tumor models. Improved survival was observed with several different combinations, and synergistic efficacy was indicated using the Chou-Talalay method [4]. These studies provide data and rationale for combining poxvirus-based immunotherapies with a variety of ICIs in the clinic.

Authors’ Affiliations

(1)
Bavarian Nordic, Inc., USA

References

  1. Madan RA, et al.: Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2012, 13 (5): 501-508. 10.1016/S1470-2045(12)70006-2.View ArticlePubMedGoogle Scholar
  2. Kantoff PW, et al.: Overall Survival Analysis of a Phase II Randomized Controlled Trial of a Poxviral-Based PSA-Targeted Immunotherapy in Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol. 2010, 28 (7): 1099-1105. 10.1200/JCO.2009.25.0597.PubMed CentralView ArticlePubMedGoogle Scholar
  3. Foy SP, et al.: Submitted, and ASCO Annual Meeting. 2014, Abstract 3013Google Scholar
  4. Chou T-C, et al.: Combined Treatment of Pancreatic Cancer with Mithramycin A and Tolfenamic Acid Promotes Sp1 Degradation and Synergistic Antitumor Activity. Cancer Res. 2010, 71 (7): 2793View ArticleGoogle Scholar

Copyright

© Foy et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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