Toll-Like Receptor 4 Agonist Injection With Concurrent Radiotherapy in Patients With Metastatic Soft Tissue Sarcoma

Abstract

ImportanceMetastatic 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.ObjectiveTo 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 ParticipantsThis 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.InterventionsTwo 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 MeasuresPrimary 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.ResultsTwelve 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 RelevanceIn 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 RegistrationClinicalTrials.gov Identifier: NCT02180698

Local Immunoradiotherapy in Patients With Metastatic Soft-Tissue Sarcoma

“…The authors also described that the pooled mean percent change in the size of lesions at last follow-up were higher in the immunoradiotherapy group compared with 3 prior irradiated lesions from 3 different patients. In the Abstract Conclusion, the authors stated that TLR4 immunoradiotherapy combinations provided better durable local control than radiotherapy alone …”

“…To the Editor Seo et al should be commended for reporting on a phase 1 trial that assessed an intratumoral toll-like receptor (TLR) 4 agonist immunotherapy in combination with concurrent radiation therapy, and the impressive associated translational research program. Twelve superficial metastatic lesions were treated and objective responses were observed in 4 lesions (1 complete response and 3 partial responses).…”

“…Former clinical trials evaluating other TLR agonists in situ with low-dose (2 × 2 Gy) radiotherapy were illustrated by massive responses of unirradiated and noninjected tumors . It would therefore be of interest to observe if clinical responses also occurred within nonirradiated/noninjected tumors in the current clinical trial, which would then argue for the induction of a systemic antitumor immunity.…”

Local Immunoradiotherapy in Patients With Metastatic Soft-Tissue Sarcoma—Reply

“…In Reply We sincerely thank Levy et al for their comments regarding radiotherapy in the setting of our phase 1 single-arm study of intratumoral (IT) TLR4 agonist injection with GLA-SE in metastatic sarcomas . We value the authors’ questions about the radiotherapy doses and ranges delivered to the target lesions after IT GLA-SE.…”

“…Our study was only designed to test the safety and tolerability of IT GLA-SE with concurrent radiation in a dose-escalation design while exploring the effect of the tumor microenvironment and T-cell receptor repertoire, and it is difficult to tease apart the effect of radiation dose in a pilot trial of this size. We selected these radiation doses because they could be given as standard of care and because there are existing data regarding how they affect the sarcoma microenvironment .…”