Research Spotlight: Improving Liver Cancer Outcomes Through Enhanced Immunotherapy

Dan G. Duda, DMD, PhD, of the Edwin L. Steele Laboratories for Tumor Biology and Department of Radiation Oncology at Massachusetts General Hospital, is the corresponding author of a paper published in Cancer Immunology Research, “Combination CXCR4 and PD1 Blockade Enhances Intratumoral Dendritic Cell Activation and Immune Responses Against Hepatocellular Carcinoma.”

 

How would you summarize your study for a lay audience?

Immunotherapy has revolutionized the management of cancer, including liver 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. Here, we report a strategy to increase the activity of dendritic cells and improve immunotherapy for liver cancer.

 

What knowledge gap does your study help to fill?

Liver 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 poor. Importantly, hepatocellular carcinoma (HCC), the most common form of liver cancer, is now the fifth leading cause of cancer-related deaths in the United States and is projected to rise to the third by 2040, underscoring the urgent need for advancements in its treatment. Our previous reports have focused on the tumor microenvironment in liver cancer, including the role of CXCR4, a receptor for CXCL12, which helps weaken the immune system’s ability to fight cancer, making it easier for the tumor to grow and spread. However, CXCR4 inhibition alone has been largely ineffective across multiple cancer models, suggesting that CXCR4 targeting should be tested in combination with other strategies.

 

What approach did you use?

In this study, we tested a combination blockade of PD1, a protein on the surface of immune cells that can suppress the immune system’s ability to fight cancer, and CXCR4. This study tested the effect of specifically blocking CXCR4 on standard anti-PD1 immunotherapy in liver cancer 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. We reasoned that using antibodies with a long half-life and specificity would help elucidate the relationship between CXCL12/CXCR4 signaling and the liver cancer microenvironment, reduce off-target effects, and improve effectiveness.

What did you find?

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.

What are the implications?

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. This effect is associated with increased infiltration and activation of cytotoxic T lymphocytes and prolonged survival. These new insights into the role of CXCR4 in dendritic cells may help improve the therapeutic efficiency of standard immunotherapy for liver cancers, in which dendritic cells are scarce.

What are the next steps?

A phase I clinical trial led by Ilyas Sahin, MD, is currently being planned at Mass General Brigham to explore the clinical potential of this promising combination therapy and address the critical need for more effective treatments in liver cancer.

Authorship: In addition to Duda, Mass General Brigham authors include Satoru Morita, Pin-Ji Lei, Kohei Shigeta, Tomofumi Ando, Tatsuya Kobayashi, Hiroto Kikuchi, Aya Matsui and Peigen Huang.

Paper cited: Morita S et al. “Combination CXCR4 and PD1 Blockade Enhances Intratumoral Dendritic Cell Activation and Immune Responses Against Hepatocellular Carcinoma.” Cancer Immunology Research DOI: 10.1158/2326-6066.CIR-24-0324

Funding: This study was supported by Bristol Myers Squibb through a sponsored research agreement; Bristol Myers Squibb provided the murine antibodies for the treatment and financial research support for the preclinical studies. This work was supported by National Institute of Health and Department of Defense grants to Duda, postdoctoral fellowships from the Japan Society for the Promotion of Science (JSPS), Takeda Science Foundation, MGH Fund for Medical Discovery Fundamental Research, and Uehara Memorial Foundation.

Disclosures: Duda reports research grants from Bayer, Surface Oncology, and Exelixis outside the published work. No disclosures were reported by the other authors.