期刊
CLINICAL CANCER RESEARCH
卷 27, 期 10, 页码 2755-2763出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-20-3435
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资金
- Lytix Biopharma AS
- United Kingdom Department of Health via the National Institute for Health Research (NIHR) Biomedical Research Centre
- King's College London
- King's College Hospital NHS Foundation Trust (NIHR Clinical Research Facility)
- Cancer Research UK
- UK Departments of Health
The study demonstrated that local administration of LTX-315 in patients with advanced solid tumors was well-tolerated and safe, with evidence of changes in the tumor microenvironment and immune-mediated anticancer activity. Analysis showed that LTX-315 induced necrosis and CD8(+) T-cell infiltration within the tumor microenvironment, as well as significant expansion of T-cell clones in peripheral blood.
Purpose: LTX-315 is a first-in-class, 9-mer membranolytic peptide that has shown potent immunomodulatory properties in preclinical models. We conducted a phase I dose-escalating study of intratumoral LTX-315 administration in patients with advanced solid tumors. Patients and Methods: Thirty-nine patients were enrolled, receiving LTX-315 injections into accessible tumors. The primary objective was to assess the safety and tolerability of this approach, with antitumor and immunomodulatory activity as secondary objectives. Tumor biopsies were collected at baseline and posttreatment for analysis of immunologic parameters. Results: The most common treatment-related grade 1-2 adverse events were vascular disorders including transient hypotension (18 patients, 46%), flushing (11 patients, 28%), and injection site reactions in 38% of patients. The most common grade 3 LTX-315-related toxicities were hypersensitivity or anaphylaxis (4 patients, 10%). Analysis of immune endpoints in serial biopsies indicated that LTX-315 induces necrosis and CD8(+) T-cell infiltration into the tumor microenvironment. Sequencing of the T-cell receptor repertoire in peripheral blood identified significant expansion of T-cell clones after treatment, of which 49% were present in available tumor biopsies after treatment, suggesting that they were tumor associated. Substantial volume reduction (>= 30%) of injected tumors occurred in 29% of the patients, and 86% (12/14 biopsies) had an increase in intralesional CD8(+) T cells posttreatment. No partial responses by immune-related response criteria were seen, but evidence of abscopal effect was demonstrated following treatment with LTX-315. Conclusions: LTX-315 has an acceptable safety profile, is clinically active, induces changes in the tumor microenvironment and contributes to immune-mediated anticancer activity.
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