The turbulence of the tumor environment will enhance the effectiveness of existing therapeutics for liver cancer

The turbulence of the tumor environment will enhance the effectiveness of existing therapeutics for  ...

A new therapeutic strategy for hepatocellular cancer (HCC) developed by an immune checkpoint inhibitor before using a multikinase inhibitor medication, according to a Massachusetts General Hospital (MGH) study. Several studies have shown that the new sequencing approach enhanced the effectiveness of the dual drug therapy, potentially prolonging the prolonged use of medications and thus reducing toxic drug exposure.

According to Dan G. Duda, PhD, a senior author of translational research in GI Radiation Oncology, and said a regimen of a multikinase inhibitor followed by an immune checkpoint blockade has historically been the way to begin testing new therapies in HCC patients. However, no one knew exactly what the effect might be of reversing these therapies.

Duda has decided to investigate by conducting a retrospective examination of patients who had been treated under the reversed, non-standard sequence. After discovering that it produced beneficial results in a cohort of 25 HCC patients, the Dudas team expanded its study to preclinical methods of HCC in mice. We found that using an immune checkpoint blockade enhanced the effectiveness of sorafenib, a standard multikinase inhibitor drug with anti-VEGFR activity, and obtained superior results.

HCC is the second deadliest type of cancer, responsible for more than 700,000 deaths globally each year. It is also the most common form of liver cancer, thanks to its immune checkpoint inhibitions. Last year, a Dudas lab found that an immune checkpoint inhibitor helps to re-adjust cancer cells and increase tumor infiltration. It was this discovery that encouraged the MGH team to modify the sequencing of the immune checkpoint inhibitor and multikinase inhibitor to see what might happen in preclinical experiments.

According to Duda, increasing CD8 T cell infiltration allows for sorafenib therapy to be administered sequentially, meaning that after anti-PD-1 therapy priming. This method was demonstrated by our findings that the depletion of the CD8 T cells erased the benefits of sorafenib in this model.

Duda believes that a new treatment strategy may be applicable in other forms of liver cancer, especially metastatic cancer, where a recent Japanese study demonstrated the effectiveness of combining immunotherapy with regorafenib, a multikinase inhibitor. Unlike chemotherapy, patients were using a less is more approach which involves the body''s immune system to reprogram the tumor environment, according to Duda. And that shows promise of reduction as well as the toxicity that often precedes prolonged therapy.

Duda is an associate professor of radiation oncology at Harvard Medical School. Lead author Hiroto Kikuchi, MD, is currently a surgeon at Keio University in Japan. Other co-authors include Aya Matsui, PhD, and Rakesh K. Jain, the professor of science at Harvard Medical School, and Thomas Yau, an associate professor at the Queen Mary Hospital, Hong Kong.

Under a sponsored research agreement with Duda, Bayer HealthCare Pharmaceuticals Inc. supported the preclinical study.

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