Abstract B56: An immuno-gene therapy clinical trial evaluating in situ vaccination of malignant pleural mesothelioma with intrapleural delivery of adenovirus-interferon-alpha-2b in combination with chemotherapy
Authors: Sterman D. H. , Alley E. , Friedberg J. , Metzger S. , Stevenson J. , Moon E. , Haas A. R. , Vachani A. , Katz S. I. , Cheng G. , Sun J. , Heitjan D. F. , Litzky L. , Cengel K. , Simone C. B. , Culligan M. , Culligan M. , Albelda S. M. 
Published: October 2015

Abstract
Background: “In situ vaccination” immune-gene therapy has the ability to induce broad, polyclonal anti-tumor responses directed by the patient's own immune system using standard “off the shelf” agents. In this trial, we activated endogenous tumor immunity by injection of an adenovirus expressing a Type I interferon into the pleural space of patients with malignant pleural mesothelioma (MM). Based on preclinical data showing synergy with chemotherapy, all patients then received standard systemic cytotoxic therapy.
Methods: Two doses of intrapleural administration of a replication-defective recombinant adenoviral vector containing the human interferon-alpha (hIFN-α2b) gene at a dose of 3x1011 viral particles were given concomitant with a 14-day course of high-dose cyclo-oxygenase-2 (COX-2) inhibitor (Celecoxib) to reduce side effects and to modify the tumor microenvironment by decreasing PGE- 2 levels. This was followed by standard first-line or second-line chemotherapy agents. Primary outcome measures were safety, overall best response rate, and survival. Bio-correlates were measured.
Results: Forty patients were treated in this study: 18 patients received first-line Pemetrexed-based chemotherapy; 7 patients who had previously received front-line Pemetrexed-based chemotherapy &gt;6 months prior to enrollment received Pemetrexed-based second-line chemotherapy. Additionally, in the second-line chemotherapy arm, fifteen patients (n=15) received gemcitabine-based chemotherapy. Treatment was well tolerated and adverse events were comparable to historical controls. Follow-up chest CT scans demonstrated an overall response rate of 20% by Modified RECIST criteria and disease control rate (DCR) of 85% (partial and complete responses plus stable disease) at initial follow-up scan after the first two cycles of chemotherapy. Encouragingly, median survival for all patients with epithelial histology (including both first and second line) was 26 months (95% CI: 15-ND); median overall survival (MOS) for patients with non-epithelial histology (both first and second line) was 6.5 months (95% CI: 5.50 – ND). [See figure] Historical MOS with first line chemotherapy alone is 13.3 months. No clear predictors for response were identified including: baseline immunologic parameters (i.e. activated T cells or number of regulatory T cells); the presence of the immune-gene signature in their biopsies; peak levels of interferon in blood or pleural fluid; or induction of anti-tumor antibodies, activated T cells, or natural killer cells in peripheral blood.
Conclusions: The combination of intrapleural Ad.IFN-α2b vector, Celecoxib, and systemic chemotherapy proved safe in patients with unresectable malignant pleural mesothelioma. Overall survival rates were significantly higher than historical controls, particularly in the second-line groups. The results of this study support proceeding with a multi-center randomized clinical trial of chemo-immunogene therapy versus standard chemotherapy alone.
Citation Format: D. H. Sterman, E. Alley, J. Friedberg, S. Metzger, J. Stevenson, E. Moon, A. R. Haas, A. Vachani, S. I. Katz, G. Cheng, J. Sun, D. F. Heitjan, L. Litzky, K. Cengel, C. B. Simone, II, M. Culligan, M. Culligan, S. M. Albelda. An immuno-gene therapy clinical trial evaluating in situ vaccination of malignant pleural mesothelioma with intrapleural delivery of adenovirus-interferon-alpha-2b in combination with chemotherapy. [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 B56.