Sequencing of Drug Combinations Could Amplify Antitumor Immune Response in Liver Cancer

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A new therapeutic strategy for hepatocellular carcinoma (HCC) that initially primes the tumor with an immune checkpoint inhibitor before using a multikinase inhibitor has shown efficacy in a study published in the Journal of the National Cancer Institute. Kikuchi et al reported that the new sequencing approach enhanced the effectiveness of the dual drug therapy, potentially allowing de-escalation of the prolonged use of medications and thus reducing toxic drug exposure.

“A regimen of a multikinase inhibitor followed by immune checkpoint blockade, alone or in combination, has historically been the way to test new treatment approaches in patients with HCC,” said Dan G. Duda, DMD, PhD, Director of Translational research in GI Radiation Oncology at Massachusetts General Hospital (MGH) and senior author of the study. “No one knew, however, what the effect might be of reversing the sequence of these therapies.”

Changing the Sequence

Dr. Duda and colleagues decided to find out by conducting a retrospective analysis of patients who had been treated under the reversed, nonstandard sequence. After learning that it produced favorable outcomes in a cohort of 25 patients with HCC, Duda’s team expanded its research to preclinical models of HCC in mice.

“We discovered that using an immune checkpoint blockade first served to amplify the immune system response, which enhanced the effectiveness of sorafenib, a standard multikinase inhibitor drug with anti-VEGFR (vascular endothelial growth factor receptor) activity, and produced superior results,” he noted.

Sorafenib became the first systemic treatment for liver cancer around 15 years ago. As an anti-VEGFR inhibitor, it works to control cancerous growth by targeting new blood vessels that feed the tumor and allow its progression. For their part, immune checkpoint inhibitors like PD-1 antibodies restore the immune system’s ability to become activated and kill cancer cells. In a major discovery last year, Dr. Duda’s lab found that immune checkpoint blockade also helps to reprogram the tumor vascular microenvironment, leading to greater T-cell infiltration and activation in HCC when used concomitantly with a multikinase inhibitor. It was that discovery that encouraged the MGH team to change the sequencing of the immune checkpoint inhibitor and multikinase inhibitor to see what would happen in preclinical models.

“We determined that increasing CD8-positive T-cell infiltration mediates the benefit of sorafenib therapy when given sequentially, meaning after anti–PD-1 therapy priming,” said Dr. Duda. “The feasibility of this approach was verified by our finding that the depletion of the CD8-positive T cells erased the benefits of sorafenib in this model.”

Dr. Duda believes the new treatment strategy could have applicability in other forms of liver cancer, particularly metastatic colorectal cancer, where a recent Japanese study showed the effectiveness of combining immunotherapy with regorafenib, another type of multikinase inhibitor.

“Unlike chemotherapy, which is geared to using the maximum tolerated dose, we’re employing a ‘less is more’ approach which uses the body’s immune system to reprogram the tumor environment,” said Dr. Duda. “And that shows great promise of reducing the doses needed for therapy as well as the toxicity that often accompanies extended use of these medicines.”

Disclosure: The preclinical study was supported by Bayer HealthCare Pharmaceuticals Inc under a sponsored research agreement with Dr. Duda. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.