Abstract CT205: Intravenous delivery of a novel oncolytic immunotherapy agent, CAVATAK, in advanced cancer patients
Authors: Pandha Hardev , Harrington Kevin , Ralph Cristy , Melcher Alan , Shafren Darren R. 
Published: August 2015

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 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 this phase I/II study advanced cancer patients received multiple intravenous (IV) doses of CAVATAK to assess treatment tolerance, levels of viral replication and viral-induced immune activation within the tumor micro-environment.
Methods: The phase I/II STORM (Systemic Treatment Of Resistant Malignancies: NCT02043665) study is investigating the tolerance of multiple escalating IV doses of CVA21 in approximately 30 advanced cancer patients. In cohort 1 (n = 3), patients were infused with CVA21 at a dose of 1 × 108 TCID50, in cohort 2 patients (n = 3) were infused with CVA21 at a dose of 3 × 108 TCID50 and treatment of patients in Cohort 3 (n = 12-18) with CVA21 at a dose of 1 × 109 TCID50 has commenced. Tumor biopsies at 8 days following the initial CVA21 infusion are being monitored for levels of virus and markers of potential immune activation. Sequential serum samples are being analyzed for viral loads, kinetics of anti-CVA21 neutralizing antibody (nAb) development and immune system activation via relative serum levels of a panel of immune inflammatory cytokines /immune cell subsets.
Results: To date, multiple CVA21 infusions of patients in Cohorts 1 and 2 have been generally well tolerated. Preliminary data indicate that the prolonged presence of serum CVA21 RNA in some, but not all, patients at times (up to 4 days post-infusion), when complete decay of the administered viral dose was expected; this may indicate possible viral replication within tumor. Such replication in pre-clinical xenograft models was potentially immunogenic, as evidenced by gene expression increases of CXCL-10 and PD-L1. Of particular interest was the finding of comparable kinetics of anti-CVA21 nAb development in patients receiving multiple infusions relative to those administered a single CVA21 infusion during a previous phase I dose-ranging study (NCT00636558). The interim data highlight a robust “multi-dosing-window” in the absence of significant levels of nAb for approximately 7 days post initial viral infusion.
Conclusion: To date, multiple IV infusions in advanced cancer patients have been generally well tolerated. Initial serum viral load data indicate potential tumor-specific CVA21 replication in some patients. Overall, the preliminary data offer an exciting possibly that tumor targeting, infection and immune activation mediated by IV CVA21 may lead to increases in anti-tumor activity, particularly when in future used in combination with immune checkpoint blockade.
Citation Format: Hardev Pandha, Kevin Harrington, Cristy Ralph, Alan Melcher, Darren R. Shafren. Intravenous delivery of a novel oncolytic immunotherapy agent, CAVATAK, in advanced cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT205. doi:10.1158/1538-7445.AM2015-CT205