Neoadjuvant Gene Mediated Cytotoxic Immunotherapy for Non-Small Cell Lung Cancer - Safety and Immunologic Activity

Lung Cancer
08/11/2020

Mol Ther. 2020 Nov 4:S1525-0016(20)30599-2. doi: 10.1016/j.ymthe.2020.11.001. Online ahead of print.

ABSTRACT

Gene-mediated cytotoxic immunotherapy (GMCI) is an immuno-oncology approach involving local delivery of a replication-deficient adenovirus expressing Herpes simplex thymidine kinase (AdV-tk) followed by anti-herpetic prodrug activation that promotes immunogenic tumor cell death, antigen presenting cell activation, and T cell stimulation. This Phase I dose escalation pilot trial assessed bronchoscopic delivery of AdV-tk in patients with suspected lung cancer who were candidates for surgery. A


single intra-tumoral AdV-tk injection in three dose cohorts (maximum 1012 viral particles) was performed during diagnostic staging, followed by a 14 day course of the prodrug valacyclovir, and subsequent surgery one week later. Twelve patients participated after appropriate informed consent. Vector-related adverse events were minimal. Immune biomarkers were evaluated in tumor and blood before and after GMCI. Significantly increased infiltration of CD8+ T cells was found in resected tumors. Expression of activation, inhibitory, and proliferation markers, such as HLA-DR, CD38, Ki67, PD1, CD39, and CTLA-4, were significantly increased in both the tumor and peripheral CD8+ T-cells. Thus, intratumoral AdV-tk injection into NSCLC proved safe, feasible, and effectively induced CD8+ T cell activation. These data provide a foundation for additional clinical trials of GMCI for lung cancer patients with potential benefit if combined with other immune therapies.