A novel strategy may increase the activity of dendritic cells and improve immunotherapy outcomes in patients with hepatocellular carcinoma, according to a recent study published by Morita et al in Cancer Immunology Research.
Background
Hepatic cancer is a disease with a poor prognosis. Despite multiple therapeutic options, including the recent emergence of immunotherapy as a first-line systemic treatment, the outcomes remain negative. Importantly, hepatocellular carcinoma—the most common type of hepatic cancer—is now the fifth leading cause of cancer-related mortality in the United States and is projected to rise to the third by 2040, underscoring the urgent need for advancements in its treatment.
Immunotherapy has revolutionized the management of cancer, including hepatic malignancies. However, the benefits are limited by multiple mechanisms of treatment resistance, including the lack of dendritic cells, which have a critical role in immune activity by helping to activate and guide other immune cells to fight infections or threats.
Previous research has focused on the tumor microenvironment in hepatic cancer, including the role of CXCR4, a receptor for CXCL12, which helps weaken the immune system’s ability to fight cancer and make it easier for the tumor to grow and spread. CXCR4 inhibition alone has been largely ineffective across multiple cancer models, suggesting that CXCR4 targeting should be tested in combination with other strategies.
PD-1 is a protein on the surface of immune cells that can suppress the immune system’s ability to fight cancer.
Study Methods and Results
In the recent study, the researchers used a combination blockade of PD-1 and CXCR4. They analyzed the efficacy of specifically blocking CXCR4 on standard anti–PD-1 immunotherapy in hepatocellular carcinoma models. Most previous studies and clinical trials tested AMD3100, a small-molecule antagonist of CXCR4, which has a short half-life and a complex mechanism of action. The researchers hypothesized that using antibodies with a long half-life and specificity would help elucidate the relationship between CXCL12/CXCR4 signaling and the hepatocellular carcinoma microenvironment, reduce off-target effects, and improve effectiveness.
The researchers discovered the potential of anti-CXCR4 to reprogram the immunologically “cold” microenvironment of hepatocellular carcinoma to an immunologically “hot” microenvironment because of its effects on dendritic cells and the benefits when combining them with anti–PD-1 therapy.
Conclusions
The findings demonstrated that combining anti-CXCR4 and anti–PD-1 therapies may be more effective compared with anti–PD-1 therapy alone in mouse models of hepatic cancer and that the increased dendritic cell activity contributed to the effectiveness of this combination therapy. This benefit was associated with increased infiltration and activation of cytotoxic T lymphocytes and prolonged survival. The researchers indicated that the new insights into the role of CXCR4 in dendritic cells may help improve the therapeutic efficiency of standard immunotherapy for hepatic cancers, in which dendritic cells are scarce.
The researchers are currently planning to conduct a phase I clinical trial to explore the clinical potential of the novel combination therapy and address the critical need for more effective treatments in hepatic cancer.
Disclosure: The research in this study was supported by Bristol Myers Squibb through a sponsored research agreement, grants from the National Institutes of Health and U.S. Department of Defense, postdoctoral fellowships from the Japan Society for the Promotion of Science, the Takeda Science Foundation, the MGH Fund for Medical Discovery Fundamental Research, and the Uehara Memorial Foundation. For full disclosures of the study authors, visit aacrjournals.org.
