Talimogene Laherparepvec Enhances the Efficacy of PD-1 Blockade

Checkpoint blockade therapies targeting PD-1 or PD-L1 achieve durable responses in a subset of patients with cancer, but tumors lacking infiltrating CD8⁺ T cells do not respond well to checkpoint blockade, suggesting that combination immunotherapy aimed at attracting CD8⁺ T cells to the tumor might enhance the antitumor activity of PD-1 blockade. The oncolytic virotherapy talimogene laherparepvec has been FDA approved for the treatment of melanoma and was designed to selectively replicate in tumors and to produce GM-CSF to promote antitumor immune responses. Thus, Ribas and colleagues performed a phase Ib trial evaluating the combination of talimogene laherparepvec and the anti–PD-1 antibody pembrolizumab in 21 patients with advanced melanoma. A run-in period with single-agent talimogene laherparepvec allowed for investigation of its effects on the tumor microenvironment before the commencement of combination therapy. Combination therapy did not result in increased toxicities compared to single-agent therapy. Responses were observed in 61.9% of patients, with complete responses occurring in 33.3% of patients. The talimogene laherparepvec run-in enhanced CD8⁺ T-cell infiltration in patients who responded to combination therapy, and responses were observed even in patients who had low baseline density of CD8⁺ T cells, lacked PD-L1 expression, or lacked the IFNγ gene expression signature (a marker of PD-L1 induction, as IFNγ stimulates PD-L1). Further, talimogene laherparepvec increased tumor-infiltrating lymphocyte density, the number of circulating T cells, and PD-L1 expression, suggesting a potential resistance mechanism that might be overcome by the addition of anti–PD-1. In addition to suggesting that combination therapy with talimogene laherparepvec plus pembrolizumab has antitumor activity in patients with advanced melanoma, these findings suggest that oncolytic virotherapy may modulate the tumor microenvironment, promoting T-cell infiltration to enhance the efficacy of PD-1 blockade.

Ribas A, Dummer R, Puzanov I, VanderWalde A, Andtbacka RH, Michielin O, et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell 2017;170:1109–1119.e10.

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