TLR9 agonist CpG and agonist anti-OX40 antibody were previously found to regress tumors and provide systemic protection after intratumoral injection. Here, Hong and Sagiv-Barfi et al. explored this treatment in a neoadjuvant setting (prior to surgery). Mice bearing CT26 or 4T1 primary tumors and metastases experienced the best survival when treated with CpG/anti-OX40 prior to tumor resection, compared to surgery or immunotherapy alone. This effect was dependent on CD8+ T cells and required a time interval between CpG/anti-OX40 injection and tumor resection. Adding anti-PD-1 therapy further improved T cell activation and 4T1 tumor control and survival.

Contributed by Alex Najibi

ABSTRACT: The combination of the synthetic TLR9 ligand CpG and agnostic OX40 antibody can trigger systemic anti-tumor immune responses upon co-injection into the tumor microenvironment, eradicating simultaneous untreated sites of metastatic disease. Here we explore the application of this in situ immunotherapy to the neoadjuvant setting. Current neoadjuvant checkpoint blockade therapy is delivered systemically, resulting in off-target adverse effects. In contrast, intratumoral immunotherapy minimizes the potential for toxicities and allows for greater development of combination therapies. In two metastatic solid tumor models, neoadjuvant intratumoral immunotherapy generated a local T cell antitumor response that then acted systemically to attack cancer throughout the body. In addition, the importance of timing between neoadjuvant immunotherapy and surgical resection was established, as well as the increased therapeutic power of adding systemic anti-PD1 antibody. The combination of local and systemic immunotherapy generated an additional survival benefit due to synergistic inhibitory effect on tumor-associated macrophages. These results provide a strong rationale for translating this neoadjuvant intratumoral immunotherapy to the clinical setting, especially in conjunction with established checkpoint inhibitors.

Author Info: (1) Surgery, Stanford University School of Medicine. (2) Department of Medicine, Stanford University. (3) Medicine/Division of Oncology, Stanford University Medical Center. (4) Dep

Author Info: (1) Surgery, Stanford University School of Medicine. (2) Department of Medicine, Stanford University. (3) Medicine/Division of Oncology, Stanford University Medical Center. (4) Department of Medicine, Division of Oncology, Stanford University. (5) Division of Oncology, Stanford University Hospital and Clinics levy@stanford.edu.