Abstract
BackgroundWe previously reported that talimogene laherparepvec, an oncolytic herpes virus encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), resulted in an objective response rate of 26 % in patients with advanced melanoma in a phase II clinical trial. The response of individual lesions, however, was not reported. Since talimogene laherparepvec is thought to mediate anti-tumor activity through both direct tumor cytolysis and induction of systemic tumor-specific immunity, we sought to determine the independent response rate in virus-injected and non-injected lesions.MethodsFifty patients with stage IIIC or IV melanoma were treated with talimogene laherparepvec in a multi-institutional single-arm open-label phase II clinical trial. In this study patients were treated until a complete response was achieved, all accessible tumors disappeared, clinically significant disease progression, or unacceptable toxicity. This report is a post hoc analysis of the systemic effects of talimogene laherparepvec in injected lesions and two types of uninjected lesions—non-visceral lesions and visceral lesions.ResultsEleven of 23 patients (47.8 %) had a ≥ 30 % reduction in the total burden of uninjected non-visceral lesions, and 2 of 12 patients (16.7 %) had a ≥ 30 % reduction in the total burden of visceral lesions. Among 128 evaluable lesions directly injected with talimogene laherparepvec, 86 (67.2 %) decreased in size by ≥ 30 % and 59 (46.1 %) completely resolved. Of 146 uninjected non-visceral lesions, 60 (41.1 %) decreased in size by ≥ 30 %, the majority of which (44 [30.1 %]) completely resolved. Of 32 visceral lesions, 4 (12.5 %) decreased in size by ≥ 30 %, and 3 (9.4 %) completely resolved. The median time to lesion response was shortest for lesions that were directly injected (18.4 weeks), followed by uninjected non-visceral lesions (23.1 weeks) and visceral lesions (51.3 weeks), consistent with initiation of a delayed regional and systemic anti-tumor immune response to talimogene laherparepvec.ConclusionsThese results support a regional and systemic effect of talimogene laherparepvec immunotherapy in patients with advanced melanoma.
Highlights
We previously reported that talimogene laherparepvec, an oncolytic herpes virus encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), resulted in an objective response rate of 26 % in patients with advanced melanoma in a phase II clinical trial
Talimogene laherparepvec contains an insertion of the human granulocytemacrophage colony-stimulating factor (GM-CSF) gene sequence at the deleted ICP34.5 coding sequence sites to enhance systemic immune response [6]
We previously reported that in a multi-institutional, single-arm, openlabel, phase II clinical trial, intralesional injection of talimogene laherparepvec resulted in an Objective response rate (ORR) of 26 % in patients with stage IIIC and stage IV melanoma
Summary
We previously reported that talimogene laherparepvec, an oncolytic herpes virus encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), resulted in an objective response rate of 26 % in patients with advanced melanoma in a phase II clinical trial. Talimogene laherparepvec, an oncolytic herpes simplex virus type 1 (HSV-1) [5], was gene modified to elicit increased selectivity and rescue replication in tumors as well as improved tumor antigen presentation It contains deletions of the neurovirulence factors ICP34.5 and a factor that blocks peptide loading onto the major histocompatibility complex (MHC) called ICP47. A randomized phase III clinical trial confirmed this objective response rate and demonstrated an especially high durable response rate for patients with stage IIIB/C and IV M1a disease [9] This trial led to the U.S Food and Drug Administration (FDA) approval of talimogene laherparepvec for local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. The ability of talimogene laherparepvec to mediate systemic clinical anti-tumor activity compared to exerting a more local effect on lymphocyte responses has been previously described [8] but not fully quantified
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