Abstract LB-123: Analyses of anti-cancer testis antigen antibodies in glioma patients treated with Delta-24 oncolytic adenovirus

Abstract

Abstract Objectives: We performed a phase I clinical trial of Delta-24-RGD, a novel tumor selective oncolytic adenovirus, in patients with recurrent malignant gliomas in order to: 1) test the safety of Delta-24-RGD after intratumoral injection; 2) determine the capability of Delta-24-RGD to induce direct oncolytic effect, and 3) ascertain if Delta-24-RGD infection results in the “unmasking” of cancer testis antigens (CTAs) and the triggering of an anti-tumor immune response. Methodology: Patients with unresectable tumors were treated with a direct intratumoral injection of Delta-24-RGD and followed for toxicity. Patients with resectable tumors underwent a two-stage approach: in stage 1, Delta-24-RGD was injected intratumorally, and in stage 2, two weeks after the injection, the tumor was resected en bloc. Surgical specimens were analyzed for viral replication using immunohistochemistry (IHC) for viral hexon protein. IHC and FACS were used to identify lymphocyte populations in resected tumors. In 20 patients, a modified solid-phase ELISA was used to detect antibodies against CTAs in the sera before and after the injection of the adenovirus. Preliminary data: 50% of patients showed radiographic responses. In a subset of these patients, there was decrease of tumor volume within weeks after Delta-24-RGD injection. In another subset there was an initial phase of pseudo-progression that lasted several weeks and was eventually followed by marked shrinkage of the tumor. One of these patients showed a complete radiographic response by 14 months after the treatment. IHC of tumor specimens documented active adenovirus replication that lasted at least for 15 days. IHC analyses showed that a subset of tumors were positive for MAGE E1. Importantly, we detected antibodies against CTAs that were present before the treatment or developed after Delta-24-RGD injection. Despite the fact that median survivals for patients with recurrent gliomas is six months, all four patients with high titers of anti-NY-ESO-1 antibodies survived after treatment: 301days (still alive), 281days (deceased), 273 days (still alive), and 126 days (still alive). Histological analyses of the post-treatment tumor from a patient with high titers of anti-NY-ESO 1, showed 80%-necrosis, striking inflammatory reaction, and predominant CD8+ lymphocytic infiltration. Conclusions: We conclude that the favorable radiographic and clinical responses of the patients treated with Delta-24-RGD adenovirus may be the result of the combination of a direct oncolytic effect and a potent adenovirus-triggered anti-tumor immunity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-123. doi:1538-7445.AM2012-LB-123