Malvehy, Josep, Samoylenko, Igor, Schadendorf, Dirk, Gutzmer, Ralf, Grob, Jean-Jacques, Sacco, Joseph J, Gorski, Kevin S, Anderson, Abraham, Pickett, Cheryl A, Liu, Kate et al (show 1 more authors)
(2021)
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.
JOURNAL FOR IMMUNOTHERAPY OF CANCER, 9 (3).
e001621-.
Abstract
<h4>Background</h4>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.<h4>Methods</h4>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<sup>+</sup> T-cell density (determined using immunohistochemistry) correlated with T-VEC clinical response.<h4>Results</h4>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<sup>+</sup> T-cell density results were available for 91 and 65 patients, respectively. Neither baseline nor change in CD8<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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.<h4>Conclusions</h4>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.<h4>Trial registration number</h4>NCT02366195.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | biomarkers, tumor, immunotherapy, melanoma, oncolytic virotherapy, T-lymphocytes |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 27 Apr 2021 14:37 |
| Last Modified: | 09 Feb 2024 01:45 |
| DOI: | 10.1136/jitc-2020-001621 |
| Open Access URL: | https://jitc.bmj.com/content/9/3/e001621 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3120757 |
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