(P 421) CHARACTERIZING THE IMMUNE RESPONSE TO INTRATUMORAL TIGILANOL TIGLATE (TT) IN PATIENTS WITH ADVANCED AND/OR METASTATIC SOFT TISSUE SARCOMA (STS) IN A PHASE IIA TRIAL (NCT05755113)

Objective: TT is an epoxytigliane small molecule that induces tumor necrosis and vascular disruption via intratumoral injection. Here we report the exploratory outcomes of a completed phase IIa clinical trial.

Methods: Eleven patients with recurrent or metastatic STS were enrolled, with one replaced, in a single arm, open label phase IIa trial of intratumoral TT dosed at 28-day intervals. The primary endpoint was the ablation rate assessed via ultrasound 28 days post injection. Immunohistochemistry (IHC) and TCRβ chain sequencing were performed on baseline and 2-week posttreatment biopsies. T cell exhaustion/activation and pan-leukocyte flow cytometry (FC) panels and TCRβ chain sequencing on gDNA were performed on blood samples collected pretreatment and at 2-, 4-, and 12-weeks posttreatment.

Results: Ten patients, 3 with leiomyosarcoma, 3 with myxofibrosarcoma, and one each of myxoinflammatory fibroblastic sarcoma, extraskeletal osteosarcoma, angiosarcoma, and sarcoma NOS were evaluable for response. Eight of 10 patients had complete or partial ablation of the injected tumor. IHC and FC demonstrated a markedly immunosuppressed phenotype at baseline, with scant intratumoral immune infiltrate and 60-80% of peripheral CD4+ and CD8+ T cells expressing the exhaustion markers CD57 and TIM3 across all patients. TCR diversity was not significantly different between pre and posttreatment blood samples. However, TCR sequencing demonstrated posttreatment enrichment in the peripheral blood of specific TCR clones found in the pretreatment tumor biopsies in 8/8 patients with evaluable samples. In one patient with biopsied distant metastases, TCR clones from the injected tumor were enriched in the periphery and increased in frequency in a non-injected tumor posttreatment.

Conclusion: Despite patients with STS having a markedly exhausted immune phenotype at baseline, intratumoral injection of TT was associated with systemic enrichment of TCR clones found in the injected tumors at baseline, suggesting a systemic immune response to intratumoral TT injection.
This trial and translational research was funded by QBiotics Group Ltd.