An international study led by researchers at Massachusetts General Hospital indicates that a combination of anti-CXCR4 and anti-PD-1 therapies may improve outcomes for hepatocellular carcinoma (HCC), the most common form of liver cancer. The research, published in Cancer Immunology Research, addresses the challenge of treatment resistance in HCC by enhancing dendritic cell activity to boost immune response.
Overcoming Immunotherapy Resistance in HCC
Liver cancer is a leading cause of cancer-related deaths globally. While immunotherapy has shown promise, its effectiveness against HCC has been limited due to the lack of immune cells in the tumor microenvironment. Dan G. Duda, DMD, PhD, the study's senior author, noted that previous research has focused on the role of CXCR4 in weakening the immune system's ability to fight cancer. "However, CXCR4 inhibition alone has been largely ineffective across multiple cancer models, suggesting that CXCR4 targeting should be tested in combination with other strategies," Duda stated.
Combination Therapy Approach
In this preclinical study, researchers tested the combination of anti-CXCR4 and anti-PD-1 therapies in mouse models. Unlike previous studies that used CXCR4 antagonists with short half-lives, this study utilized long-acting antibodies targeting CXCR4. The results showed that this combination effectively reprogrammed the "cold" liver tumor environment into one more conducive to immune response.
The combination therapy increased the presence of dendritic cells, which are crucial for initiating an immune response. Activated dendritic cells guide other immune cells, such as CD8+ T cells, to the tumor site. "We discovered the potential of anti-CXCR4 to reprogram the immunologically 'cold' microenvironment of liver cancer to an immunologically 'hot' one because of its effects on dendritic cells and the benefits when combining them with anti-PD1, a current standard therapy for patients with liver cancer," explained Duda.
Enhanced Immune Response and Clinical Implications
Further research revealed that anti-CXCR4 treatment not only promoted dendritic cell activation but also enhanced their ability to produce chemokines, attracting more immune cells into the tumor. This synergy between anti-CXCR4 and anti-PD-1 therapy resulted in better anti-cancer responses compared to anti-PD-1 therapy alone. The study demonstrated that combining anti-CXCR4 and anti-PD-1 is more effective than anti-PD-1 alone in mouse models of liver cancer, with increased infiltration and activation of cytotoxic T lymphocytes and prolonged survival.
"Our study demonstrates that combining anti-CXCR4 and anti-PD1 is more effective than anti-PD1 alone in mouse models of liver cancer, and that the increased dendritic cell activity contributes to the effectiveness of this combination therapy," Duda added. A Phase I clinical trial, led by Ilyas Sahin, MD, is being planned at Mass General Brigham to evaluate the safety and efficacy of this combination therapy in humans.
