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Combination of a novel oncolytic immunotherapeutic agent, CAVATAK (coxsackievirus A21) and immune-checkpoint blockade significantly reduces tumor growth and improves survival in an immune competent mouse melanoma model

  • 1,
  • 2,
  • 2,
  • 3,
  • 4 and
  • 2
Journal for ImmunoTherapy of Cancer20142(Suppl 3):P125

https://doi.org/10.1186/2051-1426-2-S3-P125

Published: 6 November 2014

Keywords

  • Melanoma
  • Advanced Melanoma
  • Mouse Melanoma Model
  • Advanced Melanoma Patient
  • Immune Competent Mouse

Coxsackievirus A21 (CAVATAK™) is a bio-selected oncolytic immunotherapy virus. Following intratumoral (i.t) injection, CAVATAK selectively infects ICAM-1-expressing tumor cells, resulting in tumor cell lysis and a systemic immune-mediated anti-tumor response. A Phase II trial of i.t delivered CAVATAK (NCT01227551) in advanced melanoma patients has highlighted antitumor activity in both injected and distant non-injected lesions. Such responses have occurred at times when no circulating infectious CAVATAK was detected in patient serum and in an environment of high levels of anti-CAVATAK neutralizing antibodies. In further support of the generation of CAVATAK-mediated immune anti-tumor activity is the identification of a possible novel serum cytokine signature of elevated levels of IL-8 and IFN-γ in treated patients associated with tumor inflammation and systemic tumor response. Blockade of programmed death-1 (PD-1) in patients with metastatic melanoma has resulted in substantial tumor responses via a mechanism involving reversal of tumor-induced T cell suppression. We hypothesized that a combination of CAVATAK and PD-1 blockade may enhance anti-tumor responses, potentially leading to improved clinical activity. Preclinical studies in C57BL mice were conducted to assess the anti-tumor activity of CAVATAK and anti-mouse PD-1 (mPD-1) mAb in a B16-ICAM-1 melanoma immune competent mouse model. B16-ICAM-1 cells are murine melanoma B16 cells stably transfected to express human ICAM-1 allowing CAVATAK binding and cell infection. CAVATAK was administered i.t, while anti mPD-1 mAb was delivered intraperitoneally. Following treatment of the primary cutaneous B16-ICAM-1 tumor with 8 cycles of CAVATAK injections and 4 cycles of anti-PD-1mAb, mice were challenged with additional subcutaneous administration of B16 cells. Significant single agent anti-tumor activities against the primary B16-ICAM-1 tumor were observed in mice treated with either CAVATAK or anti-PD-1 mAb relative to saline controls. Combination of CAVATAK and anti-PD-1 mAb mediated significantly greater anti-tumor activity and offered greater survival benefit when compared to use of either agent alone. Of particular interest was the finding that a combination of CAVATAK and anti-PD-1 mAb was able to noticeably delay the onset of palpable tumor development following B16 cell challenge when compared to all other single agent treatment regimes. The significant anti-tumor activity mediated by the combination of CAVATAK and the checkpoint inhibitor antibody (anti-PD-1) observed in the presented murine melanoma model supports clinical evaluation of such an immunotherapeutic combination treatment regimen in patients with advanced melanoma.

Authors’ Affiliations

(1)
Viralytics, Sydney, Australia
(2)
School of BioMedical Sciences and Pharmacy, The University of Newcastle, New Lambton Heights, Australia
(3)
Huntsman Cancer Institute, Salt Lake City, USA
(4)
Rutgers Cancer Institute of New Jersey, New Brunswick, USA

Copyright

© Shafren 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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