Abstract CT214: Phase II CALM study: Changes in the tumor microenvironment induced by the immunotherapeutic agent coxsackievirus A21 delivered intratumorally in patients with advanced melanoma
Authors: Andtbacka Robert , Curti Brendan , Hallmeyer Sigrun , Shafren Darren R. 
Published: August 2015

Abstract
Background: CAVATAK, an oncolytic immunotherapy, is a bio-selected oncolytic strain of coxsackievirus A21 (CVA21). Following intratumoral (IT) injection, CVA21 preferentially infects ICAM-1 expressing tumor cells, resulting in viral replication, cell lysis, and a systemic antitumor immune response. The phase II CALM study investigated the efficacy and safety of IT CVA21 in pts with advanced melanoma. The primary endpoint of the study was achieved with 22 of 57 (38.6%) evaluable pts displaying immune-related PFS (irPFS) at 6 months. Preliminary analysis of secondary endpoints showed: median irPFS of 4.2 months (95% CI 2.8, 8.3), 1-year survival 75.0% (36 of 48 pts), on-going best objective response rate of 28.1% (16 of 57 pts), median time to response 2.8 months. Responses were observed in both injected and non-injected melanoma metastases. Here we report on a continuation study aimed at understanding the immune mediated effects of CVA21.
Methods: To further elucidate the nature of the systemic antitumor responses, a CALM study extension cohort of 12 pts will receive up to 3 × 108 TCID50 CVA21 IT on study days 1,3,5 and 8 and then every three weeks for a further 6 injections. Sequential tumor biopsies of both injected and non-injected lesions will be monitored for levels of viral replication and evidence of viral-induced immune activation within the tumour micro-environment. Serial serum samples are being monitored for viral loads, anti-CVA21 neutralizing antibody (nAb) and levels of immune-inflammatory cytokines.
Results: Active tumor-specific cytolytic viral replication is postulated to contribute to the generation of systemic antitumor responses. Normal kinetics of CVA21 decay would lead to complete viral clearance from the circulation around 24-30 hrs post-viral administration. Preliminary serum testing of CALM study pts for CVA21 load by viral-RNA RT-PCR revealed that at 48 hrs post-IT injection on treatment days 1 and 3, 40% and 42% of pts respectively possessed circulating CVA21, indicating possible tumor-specific cytolytic viral replication and detection of progeny virus. Detection of persistent serum CVA21 levels reduced to approx. 14% of pts at study day 8, a time where significant levels of anti-CVA21 nAb started to develop. Elevated levels of the inflammatory cytokines γ-IFN and IL-8 in the serum of some of these pts at similar time points provides further evidence for active viral infection and potential immune activation.
Conclusions: Preliminary data indicate possible cytolytic-tumor specific CVA21 replication in a number of treated patients. Serial biopsies of CVA21-injected and non-injected lesions of advanced melanoma pts are being examined to confirm the nature of IT viral replication and its direct impact on immune activation in the tumor micro-environment and generation of potential systemic antitumor immune responses.
Citation Format: Robert Andtbacka, Brendan Curti, Sigrun Hallmeyer, Darren R. Shafren. Phase II CALM study: Changes in the tumor microenvironment induced by the immunotherapeutic agent coxsackievirus A21 delivered intratumorally in patients with advanced melanoma. [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 CT214. doi:10.1158/1538-7445.AM2015-CT214