Abstract 2939: CAVATAK-mediated oncolytic immunotherapy in advanced melanoma patients
Authors: Robert H. Andtbacka, Darren R. Shafren, Mark Grose, Len Post, Jeffrey Weisberg
Journal: Cancer Research (2014)

Abstract Background: Coxsackievirus A21 (CVA21) is a naturally occurring “common cold” intercellular adhesion molecule-1 (ICAM-1) targeted RNA virus. Surface ICAM-1 is up-regulated on a number of cancers including melanoma, non-small cell lung, bladder, breast and prostate cancers. CAVATAK is a novel bio-selected formulation of CVA21, which displays potent oncolytic activity against in vitro cultures of cancer cells and in vivo xenografts of a number of cancers. In addition, in vivo tumor challenge studies in immune-competent mouse models have shown that CVA21 lysed tumor cells can induce a secondary systemic host-generated anti-tumor immune response. In this report, advanced melanoma patients were administered multiple intralesional injections of CAVATAK and monitored for markers of host anti-tumor activity on metastatic non-injected lesions. Methods: The Phase II CALM (CAVATAK in Late stage Melanoma) study is investigating the efficacy and safety of intratumoral CAVATAK in 54 advanced melanoma patients. Patient tumors are injected with up to 3 x 10e8 TCID50 CAVATAK on study days 1, 3, 5, 8 and 22 then every 3 weeks for a further 5 injections. CAVATAK-mediated immune anti-tumor activity was assessed by monitoring reductions in non-injected lesions (CT-scan and callipers) and assessing the relative serum levels of a panel of immune inflammatory cytokines. In addition, levels of serum CAVATAK and anti-CAVATAK neutralizing antibodies were assessed on multiple occasions prior to intralesional injections. Results: Intralesional CAVATAK injections resulted in significant responses in a number of melanoma lesions. However, in addition to melanoma tumor responses directly from CAVATAK-mediated oncolysis, a number of non-injected metatastic lesions displayed significant reductions or even complete destruction. Such anti-tumor activity in non-injected lesions is highly suggestive of being mediated via a host generated anti-tumor immune response. 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 antibody. In further support of the generation of CAVATAK-mediated immune anti-tumor activity is the identification a possible novel serum cytokine signature of elevated levels of IL-8 and γ-IFN in treated patients linked to systemic tumor response. IL-8 is known to be secreted by activated macrophages, while γ-IFN is produced by stimulated cytotoxic T-cells / NK cells. Conclusion: With a number of patients in the Phase II CALM study displaying reductions in non-injected lesions, together with elevated serum levels of the immune inflammatory cytokines IL-8 and γ-IFN, at times with no detectable levels of circulating infectious CAVATAK, we conclude the generation of a targeted CAVATAK-mediated host anti-tumor response acting on metastatic melanoma lesions is highly likely. Clinical trial information: NCT01227551. Citation Format: Robert H. Andtbacka, Darren R. Shafren, Mark Grose, Len Post, Jeffrey Weisberg. CAVATAK-mediated oncolytic immunotherapy in advanced melanoma patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2939. doi:10.1158/1538-7445.AM2014-2939