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

Abstract

BackgroundTalimogene 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.MethodsIn 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.ResultsOf 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.ConclusionsThis 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 numberNCT02366195.

Oncolytic HSV: Underpinnings of Tumor Susceptibility

“…The study recorded an objective response rate of 28% and a complete response rate of 14%, which is on par with previous T-VEC melanoma trials [ 139 , 140 , 141 ]. Intriguingly, there was a 2.4-fold increase in T lymphocyte infiltration in non-injected lesions 6 weeks after initial treatment yet, CD4+ or CD8+ T lymphocyte infiltration did not correlate with the objective response rate [ 139 ]. Notably, activated T lymphocytes secreting IFN-γ can upregulate PDL1 expression in the epithelium as a negative feedback mechanism to control hyperactivation [ 133 ].…”

“…To further examine the immune effectors driving antitumor responses with T-VEC monotherapy, a recently completed Phase II clinical trial analyzed the correlates between immune cell infiltration and objective response rate in individuals with stage IIIB-IVM1a melanoma [ 139 ]. The study recorded an objective response rate of 28% and a complete response rate of 14%, which is on par with previous T-VEC melanoma trials [ 139 , 140 , 141 ].…”

“…To further examine the immune effectors driving antitumor responses with T-VEC monotherapy, a recently completed Phase II clinical trial analyzed the correlates between immune cell infiltration and objective response rate in individuals with stage IIIB-IVM1a melanoma [ 139 ]. The study recorded an objective response rate of 28% and a complete response rate of 14%, which is on par with previous T-VEC melanoma trials [ 139 , 140 , 141 ]. Intriguingly, there was a 2.4-fold increase in T lymphocyte infiltration in non-injected lesions 6 weeks after initial treatment yet, CD4+ or CD8+ T lymphocyte infiltration did not correlate with the objective response rate [ 139 ].…”

“…Exploratory analysis revealed detectable PDL1 expression in non-injected lesions of 10/50 patients at baseline, and this increased to 28/50 patients after 6 weeks of T-VEC treatment. This is suggestive of adaptive resistance to T lymphocyte infiltration in which malignancy upregulates immune checkpoints in non-injected lesions of patients treated with T-VEC [ 139 ]. This study reinforces combination therapy approaches using immune checkpoint inhibitors (anti-PD1/PDL1) and provides initial evidence to explain the synergistic effects seen when combining T-VEC with checkpoint blockade (Phase 1b: T-VEC in combination with anti-PD1 for advanced melanoma: objective response rate 62%, complete response rate 33%) [ 142 ].…”

Insights Into Dendritic Cells in Cancer Immunotherapy: From Bench to Clinical Applications

“…Cancer evades immune surveillance as one of its hallmarks and prevents the immune system from tumor eradication ( Hanahan and Weinberg, 2011 ; Mittal et al, 2014 ). Thus, immunotherapy, relying on cell therapy, cancer inhibitory signal antagonists, nanoparticle-based vaccines, oncolytic viruses, and immunogenic cell death-inducing agents, is considered a cornerstone in cancer treatment ( Helmy et al, 2013 ; Yang, 2015 ; Kranz et al, 2016 ; Van der Jeught et al, 2018 ; Riley et al, 2019 ; Vanmeerbeek et al, 2020 ; Malvehy et al, 2021 ). In general, cell-based cancer immunotherapy can be divided into two subclasses, active and passive immunotherapies.…”