Pre-operative intratumoral toll-like receptor 9 (TLR9) agonist vidutolimod (Vidu) and stereotactic body radiation therapy (SBRT) in early triple-negative breast cancer (eTNBC): Randomized phase 2 CyberImmunoBreast trial.

Abstract

e12635 Background: Vidu is a virus-like particle encapsulating a TLR9 agonist, CpG-A, promoting Th1-based innate and adaptive immune responses. Vidu showed antitumor activity in patients with PD-1/PD-L1 inhibitor-resistant melanoma. Irradiation is considered as a potential anti-tumor immune-stimulator. We assess the ability of these two modalities to increase stromal tumor-infiltrating lymphocytes (sTILs), a biomarker associated with improved outcomes in eTNBC (NCT04807192). Methods: Untreated eTNBC patients are randomized 1:1 to SBRT (1x 8 Gy) on the tumor bed (Arm 1) vs SBRT followed by 4 doses of Vidu injected subcutaneously on D1 and intratumorally on D5, D9, and D16 (Arm 2) before surgery. Tissue and blood samples were collected at baseline (BL) and surgery. The primary endpoint is the change of sTILs from BL to surgery, with a predefined efficacy threshold of a 10% absolute mean increase. Secondary endpoints include safety and tolerability, clinical outcome parameters, and exploratory translational research, including immune cell profiling in peripheral blood, digital spatial profiling of protein and RNA expression in tissue, and assessment of T-cell receptor (TCR) diversity. We present the interim results of the first 8 patients. Results: Four patients were recruited in each arm. At BL, patients had NST histology, cN0, and median tumor size 2.2 cm (1.0-3.0). All patients with Vidu showed an increase of sTILs ranging from 10 to 75%, and also follicular and interfollicular hyperplasia in their axillary sentinel lymph node; none in the SBRT-alone arm exhibited these features. Analyzed tissue samples revealed an on-target effect of Vidu with the increase of MyD88 and decrease of IKBKG. At proteins level, the addition of Vidu to SBRT displayed an activation of INFg/IL6 pathway and higher impact on tumor proliferation, cell death and immune cells. CD4 and CD8 T-cells, memory cells, macrophages, myeloids and neutrophils were upregulated; cells expressing CD20, CD34 or CD56 were decreased. Addition of Vidu to SBRT favored the maintenance of immune checkpoint proteins expression in TME and their downregulation in tumor. At the transcriptional level, Arm 2 displayed an increase in immune response, immune receptor activity, antigen presentation, cell migration, apoptosis, and recruitment of immune cells. Decreased TCR score suggests a promotion of clonal specific T-cells. In blood, granulocytic myeloid derived suppressor cells (gMDSC) decreased in Arm 2. Conclusions: Intratumoral Vidu injection increased significantly sTILs in all treated patients and induced favorable immunological modulation of the tumor and its microenvironment. Thus, Vidu may potentially alter response to neo-/adjuvant treatments and patients’ outcomes, warranting further investigations. Clinical trial information: NCT04807192 .