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Updated: Jul 13, 2025
A Mouse Model of Incompletely Resected Soft Tissue Sarcoma for Testing Neoadjuvant Therapies
Published on: July 28, 2020
Toll-Like Receptor 4 Agonist Injection With Concurrent Radiotherapy in Patients With Metastatic Soft Tissue Sarcoma:
Yongwoo David Seo1,2, Hailing Lu3, Graeme Black4
1Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
Importance:
Metastatic soft tissue sarcomas (STSs) have limited systemic therapy options, and immunomodulation has not yet meaningfully improved outcomes. Intratumoral (IT) injection of the toll-like receptor 4 (TLR4) agonist glycopyranosyl lipid A in stable-emulsion formulation (GLA-SE) has been studied as immunotherapy in other contexts.
Objective:
To evaluate the safety, efficacy, and immunomodulatory effects of IT GLA-SE with concurrent radiotherapy in patients with metastatic STS with injectable lesions.
Design, Setting, And Participants:
This phase 1 nonrandomized controlled trial of patients with STS was performed at a single academic sarcoma specialty center from November 17, 2014, to March 16, 2016. Data analysis was performed from August 2016 to September 2022.
Interventions:
Two doses of IT GLA-SE (5 μg and 10 μg for 8 weekly doses) were tested for safety in combination with concurrent radiotherapy of the injected lesion.
Main Outcomes And Measures:
Primary end points were safety and tolerability. Secondary and exploratory end points included local response rates as well as measurement of antitumor immunity with immunohistochemistry and T-cell receptor (TCR) sequencing of tumor-infiltrating and circulating lymphocytes.
Results:
Twelve patients (median [range] age, 65 [34-78] years; 8 [67%] female) were treated across the 2 dose cohorts. Intratumoral GLA-SE was well tolerated, with only 1 patient (8%) experiencing a grade 2 adverse event. All patients achieved local control of the injected lesion after 8 doses, with 1 patient having complete regression (mean regression, -25%; range, -100% to 4%). In patients with durable local response, there were detectable increases in tumor-infiltrating lymphocytes. In 1 patient (target lesion -39% at 259 days of follow-up), TCR sequencing revealed expansion of preexisting and de novo clonotypes, with convergence of numerous rearrangements coding for the same binding sequence (suggestive of clonal convergence to antitumor targets). Single-cell sequencing identified these same expanded TCR clones in peripheral blood after treatment; these T cells had markedly enhanced Tbet expression, suggesting TH1 phenotype.
Conclusions And Relevance:
In this nonrandomized controlled trial, IT GLA-SE with concurrent radiotherapy was well tolerated and provided more durable local control than radiotherapy alone. Patients with durable local response demonstrated enhanced IT T-cell clonal expansion, with matched expansion of these clonotypes in the circulation. Additional studies evaluating synergism of IT GLA-SE and radiotherapy with systemic immune modulation are warranted.
Trial Registration:
ClinicalTrials.gov Identifier: NCT02180698.
Insights
Intratumoral glycopyranosyl lipid A in stable-emulsion formulation (GLA-SE) combined with radiotherapy is safe for metastatic soft tissue sarcomas. This immunotherapy approach demonstrated durable local control and enhanced antitumor immunity.
Area of Science:
- Oncology
- Immunotherapy
- Radiotherapy
Background:
- Metastatic soft tissue sarcomas (STSs) have limited treatment options.
- Immunotherapy has not significantly improved outcomes for STSs.
Purpose of the Study:
- To assess the safety, efficacy, and immunomodulatory effects of intratumoral (IT) GLA-SE with concurrent radiotherapy in metastatic STS patients.
- To evaluate IT GLA-SE in patients with injectable lesions.
Main Methods:
- Phase 1 nonrandomized controlled trial involving 12 STS patients.
- Two doses of IT GLA-SE (5 μg and 10 μg) administered weekly for 8 weeks concurrently with radiotherapy.
- Safety, local response rates, and antitumor immunity (immunohistochemistry, TCR sequencing) were assessed.
Main Results:
- IT GLA-SE was well tolerated, with only one grade 2 adverse event.
- All patients achieved local control of the injected lesion; one patient experienced complete regression.
- Durable local response correlated with increased tumor-infiltrating lymphocytes and expansion of T-cell receptor (TCR) clones in both tumor and circulation.
Conclusions:
- IT GLA-SE combined with radiotherapy is safe and offers more durable local control than radiotherapy alone for metastatic STS.
- Enhanced intratumoral T-cell clonal expansion was observed in patients with durable local responses.
- Further research into combining IT GLA-SE and radiotherapy with systemic immune modulation is warranted.
