Phase Ii Multicenter Study Of Gene-Mediated Cytotoxic Immunotherapy As An Adjuvant To Surgical Resection For Newly Diagnosed Malignant Glioma: Lessons Learned From Pseudo-Progression And A Nine-Year Survivor

Gene Mediated Cytotoxic Immunotherapy (GMCI) generates a polyvalent anti-tumor immune response via local delivery of aglatimagene besadenovec (AdV-tk) plus prodrug. The resulting cytotoxic nucleotide analog is toxic to cells as it halts DNA replication and repair. Tumor cell death releases tumor associated antigens, which are taken up by antigen presenting cells. There is a simultaneous stimulation of pro-inflammatory cytokines by thymidine kinase. The treatment mounts an immune response that is ongoing for many months to years. Extensive preclinical studies were performed, followed by a Phase II multicenter trial assess safety and overall survival (OS) after GMCI+SOC compared to a concurrent matched control group meeting protocol criteria and undergoing SOC. Ten 100 microliter injections of AdV-tk were made into the tumor resection bed followed by oral valacyclovir for 14 days. Results: Preclinical studies have documented that response to treatment is dependent on upregulation of antigen presenting cells and an immuno-modulating effect from interleukins, including IL-2 and IL-12. The response is greatly enhanced by the synergistic effect of radiation therapy initiated on day 3 after injection of therapy. CD4 helper cells did not appear to play an important role. Survival was greatly enhanced in those in whom an immune response can be documented either radiographically or histologically. 48 patients completed SOC+GMCI and 134 SOC in the matched cohort. There were no dose-limiting toxicities. Median OS increased by 3.6 months, from 13.5 for SOC to 17.1 months for GMCI+SOC (p = 0.0417). Survival at 1- 2- and 3-years increased from 57%, 22%, and 8% to 67%, 35%, and 19%, respectively. Improvement was mostly in patients who underwent gross total resection: median OS increased from 16.9 to 25 months (p = 0.0492); 1- 2- and 3-year survival rates from 64%, 28% and 6% to 90%, 53% and 32%. A number of patients had marked pseudoprogression, well beyond the RANO or iRANO criteria. The most robust response was in a nine year survivor who demonstrated a doubling of apparent enhancing tumor at three months after treatment. Enhancing tumor slowly resolved over a five year period, with complete resolution only seen in an MRI scan made nine years later. Many other patients had similar responses, with effects of treatment ongoing for many years, and an initial response falsely suggesting treatment failure. Conclusions: GMCI can be safely combined with SOC in newly diagnosed malignant gliomas. Survival rates compared favorably to historical reports and a matched control group. Survival outcomes were significantly improved in patients with minimal residual disease after total resection. The most robust responders had dramatic worsening of contrast enhancing lesions at three and six months after intervention, well beyond standard criteria utilized to distinguish between true disease and pseudoprogression. The results document efficacy of treatment, and illustrate the need for new tools for evaluation of pseudoprogression in CNS immunotherapy trials. Characteristics and factors predicting a robust response to treatment will be discussed, as well as important clinical findings in the responder population. Citation Format: David S. Baskin, Laura K. Aguilar, Lee A. Wheeler, Andrea G. Manzanera, Susan D. Bell, Robert Cavaliere, John M. McGregor, Simon S. Lo, John C. Grecula, Herbert B. Newton, Behnam Badie, Bin S. Teh, Edward Brian Butler, Todd W. Trask, Jana Portnow, Pamela Z. New, Estuardo Aguilar-Cordova, E. Antonio Chiocca. Phase II multicenter study of gene-mediated cytotoxic immunotherapy as an adjuvant to surgical resection for newly diagnosed malignant glioma: lessons learned from pseudo-progression and a nine-year survivor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT110.