Ori-Ab-003

The A-BRAVE trial evaluated the efficacy of avelumab, an anti-programmed death-ligand 1 (PD-L1) antibody, as adjuvant treatment of patients with early triple-negative breast cancer (TNBC) at high risk.

A-BRAVE is a phase III study that randomly assigned patients with high-risk early TNBC to 1 year of avelumab versus observation, after completion of standard surgery and (neo)adjuvant chemotherapy. High-risk was defined as either: (i) ≥pN2/any pT, pN1/pT2, or pN0/pT3 after primary surgery (stratum A); or (ii) invasive residual disease (breast and/or nodes) after neoadjuvant chemotherapy (stratum B). Coprimary endpoints were disease-free survival (DFS) in the intention-to-treat (ITT) and stratum B populations. Secondary endpoints were overall survival (OS) and DFS in PD-L1-positive patients. PD-L1 was evaluated in treatment-naïve tumor samples by immunohistochemistry (73-10 RUO assay, Agilent Technologies) and digital pathology.

From June 2016 to October 2020, 466 patients were randomly assigned: 383 entered stratum B (82%) and 83 entered stratum A (18%). At a median follow-up of 52.1 months, avelumab did not significantly improve DFS in the ITT population [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.61-1.09, P = 0.172; 3-year DFS estimates were 68.3% for avelumab versus 63.2%], or in stratum B (HR 0.80, 95% CI 0.58-1.10, P = 0.170; 3-year DFS estimates were 66.9% for avelumab versus 60.7%). In a descriptive analysis, avelumab reduced the hazard of OS events: HR 0.66, 95% CI 0.45-0.97. The 3-year OS estimates for avelumab and control arm were 84.8% (95% CI 79.5% to 88.8%) and 76.3% (95% CI 70.1% to 81.3%), respectively. PD-L1 status was prognostic but not predictive for avelumab benefit in terms of DFS (test for interaction P = 0.155).

For patients with TNBC at high risk of relapse who complete standard treatment with surgery and (neo)adjuvant chemotherapy, 1 year of adjuvant avelumab versus observation did not improve DFS. However, a descriptive analysis suggests a potential favorable impact on OS.

Hyperthermia using magnetic nanoparticles is a promising cancer therapy that locally destroys tumors and induces antitumor immunity by releasing tumor antigens from dying cells. However, magnetic hyperthermia in malignant melanomas with poor immunogenicity and an immunosuppressive microenvironment remains challenging. Here, all‐in‐one magnetic nanoparticles (αPD‐L1/CpG@MCL) are developed for thermo‐immunotherapy that enables hyperthermia with magnetic nanoparticles and immunotherapy with anti‐PD‐L1 antibody and CpG to improve the immunosuppressive tumor microenvironment. Magnetic hyperthermia with magnetite cationic liposomes (MCL, without anti‐PD‐L1 antibody and CpG) inhibits tumor growth in B16F10 melanoma; however, complete tumor regression is not observed. In contrast, complete tumor regression is observed when mice are treated with thermo‐immunotherapy using αPD‐L1/CpG@MCL. Additionally, mice cured after magnetic hyperthermia with αPD‐L1/CpG@MCL rejected rechallenge with B16F10 cells, and cytotoxicity assay using splenocytes from cured mice shows the induction of antitumor immunity against B16F10 cells. Analysis of tumor‐infiltrating lymphocytes reveals that magnetic hyperthermia with αPD‐L1/CpG@MCL increased CD8+ T lymphocytes and M1‐like macrophages, and decreased M2‐like macrophages, indicating an improvement in the tumor microenvironment. This study provides a key design strategy for all‐in‐one magnetic nanoparticles that could cure malignant melanomas.