Talimogene laherparepvec upregulates immune-cell populations in non-injected lesions: findings from a phase II, multicenter, open-label study in patients with stage IIIB–IVM1c melanoma
Josep Malvehy, Igor Samoylenko, Dirk Schadendorf, Ralf Gutzmer, Jean‐Jacques Grob, Joseph J. Sacco, Kevin Gorski, Abraham Anderson, Cheryl A. Pickett, Kate Liu, Helen Gogas
Abstract
Background Talimogene laherparepvec (T-VEC), an oncolytic virus, was designed to selectively replicate in and lyse tumor cells, releasing tumor-derived antigen to stimulate a tumor-specific immune response. Methods In this phase II study in patients with unresectable stage IIIB–IV melanoma, we evaluated non-injected lesions to establish whether baseline or change in intratumoral CD8 + T-cell density (determined using immunohistochemistry) correlated with T-VEC clinical response. Results Of 112 enrolled patients, 111 received ≥1 dose of T-VEC. After a median follow-up of 108.0 weeks, objective/complete response rates were 28%/14% in the overall population and 32%/18% in patients with stage IIIB–IVM1a disease. No unexpected toxicity occurred. Baseline and week 6 change from baseline CD8 + T-cell density results were available for 91 and 65 patients, respectively. Neither baseline nor change in CD8 + T-cell density correlated with objective response rate, changes in tumor burden, duration of response or durable response rate. However, a 2.4-fold median increase in CD8 + T-cell density in non-injected lesions from baseline to week 6 was observed. In exploratory analyses, multiparameter immunofluorescence showed that after treatment there was an increase in the proportion of infiltrating CD8 + T-cells expressing granzyme B and checkpoint markers (programmed death-1, programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen-4) in non-injected lesions, together with an increase in helper T-cells. Consistent with T-cell infiltrate, we observed an increase in the adaptive resistance marker PD-L1 in non-injected lesions. Conclusions This study indicates that T-VEC induces systemic immune activity and alters the tumor microenvironment in a way that will likely enhance the effects of other immunotherapy agents in combination therapy. Trial registration number NCT02366195 .