1. 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.
- Author
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Malvehy J, Samoylenko I, Schadendorf D, Gutzmer R, Grob JJ, Sacco JJ, Gorski KS, Anderson A, Pickett CA, Liu K, and Gogas H
- Subjects
- Adult, Aged, Aged, 80 and over, Biological Products adverse effects, Europe, Female, Herpesvirus 1, Human pathogenicity, Humans, Male, Melanoma immunology, Melanoma pathology, Melanoma virology, Middle Aged, Neoplasm Staging, Oncolytic Viruses pathogenicity, Skin Neoplasms immunology, Skin Neoplasms pathology, Skin Neoplasms virology, Time Factors, Treatment Outcome, Biological Products therapeutic use, CD8-Positive T-Lymphocytes immunology, Herpesvirus 1, Human immunology, Lymphocytes, Tumor-Infiltrating immunology, Melanoma therapy, Oncolytic Virotherapy adverse effects, Oncolytic Viruses immunology, Skin Neoplasms therapy, Tumor Microenvironment immunology
- 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., Competing Interests: Competing interests: JM has acted as a consultant/advisor for and has received honoraria from Almirall, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Leo Pharma, Novartis, Pierre Fabre and Roche. IS has acted as a consultant and served on a speaker’s bureau for Biocad, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis and Roche. DS has received research support from Bristol-Myers Squibb and Novartis; has acted as a consultant for and received royalties from Amgen, Array, AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Roche; and has acted as a consultant for Immunocore, Incyte, LeoPharma, Merck Serono, Pfizer, Philogen, and Regeneron. RG has received research support from Johnson & Johnson, Novartis, Merck Serono, Amgen and Pfizer; has received honoraria for advice and/or lectures from Almirall Hermal, Amgen, Bayer, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi/Regeneron, SUN Pharma and 4SC. J-JG has acted as a consultant/in an advisory role for and has received honoraria from Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Merck-Pfizer, Pierre Fabre, and Roche. JJS has received research support from AstraZeneca, Bristol-Myers Squibb and Immunocore; has acted as a consultant/in an advisory role for Immunocore, Delcath, Merck Sharp & Dohme, Amgen and Pierre Fabre; and served on a speaker’s bureau for Bristol-Myers Squibb. KSG and AA are employees and stock holders of Amgen. KL is an employee of Amgen. CAP was previously an employee of Amgen. HG has acted as a consultant/in an advisory role for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Amgen, Roche and Pierre Fabre., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2021
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