Background: Gene therapy with oncolytic viruses is a promising novel treatment modality for cancer due to their selective replication and lytic effect on cancer cells. Although the clinical safety profiles of individual agents are encouraging, the efficacy of oncolytic viruses as monotherapy has been limited. Arming the virus with an immune stimulatory molecule is an appealing strategy and may increase overall antitumor potency. Granulocyte-macrophage colony-stimulating factor (GMCSF) is one of the most potent inducers of antitumor immunity. GMCSF is associated with recruitment and maturation of antigen presenting cells (APCs), mainly dendritic cells, as well as activating the innate immunity by recruiting natural killer cells and neutrophils. Local GMCSF expression could ensure sufficient local concentration for induction of an anti-tumor immune response circumventing the problems with toxic systemic exposure and side effects.
Results: 5/3 chimeric oncolytic adenovirus selective for the p16-Rb pathway engineered to contain a tumor specific E2F promoter and carrying GMCSF (Ad5/3-hTERT-E2F-Δ24-GMCSF aka. CGTG-602) was constructed. Preclinical studies in vivo showed promising efficacy in immune competent Syrian hamster model. Encouraged by these results, 13 patients were treated with Ad5/3-hTERT-E2F-Δ24-GMCSF in Advance Therapy Access Program. Treatments were well-tolerated and overall signs of antitumor efficacy were seen in 9/12 patients (75%) when evaluated by PET-CT or tumor markers. Patient samples were analyzed for virus circulation in blood, neutralizing antibody titers, tumor- and adenovirus-specific PBMCs and antibodies against selected tumor associated antigens. Microarray analysis and immunohistochemistry were performed on available tumor biopsies and indicated accumulation of immunological cells, especially T-cells, to tumors after treatment. RNA expression analyses of tumors indicated immunological activation and metabolic changes secondary to virus replication.
Conclusions: These findings demonstrate that Ad5/3-hTERT-E2F-Δ24-GMCSF was safe and able to show promising signs of efficacy in preclinical studies and in patients. Clinical trials are needed to confirm these preliminary findings in larger patient cohorts.
Citation Format: Otto Hemminki, Suvi Parviainen, Akseli Hemminki. Patients treated with oncolytic adenovirus Ad5/3-hTERT-E2F-Δ24-GMCSF induce immunological antitumor responses. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B80.
- ©2015 American Association for Cancer Research.