A new strategy for treating hepatocellular tumors (HCC), which first injects the tumors with an immune checkpoint inhibitor, before adding a multikinase inhibitor drug, showed great promise in treating patients with this deadly disease. A Paper published in Journal of the National Cancer InstituteResearchers found that the new sequencing approach increased the effectiveness and efficacy of dual drug treatment. This could potentially allow for the de-escalation or reduction in prolonged use of drugs, and therefore reduce toxic drug exposure.
A combination of a multikinase inhibitor and immune checkpoint blockingade has been used historically to test new treatment options in HCC patients. Dan G. Duda is DMD, PhD, director for translational research in GI Radiation Oncology (MGH) and senior author of this study. The effect of reversing this sequence of therapies was not known.
Duda conducted a retrospective analysis on patients who were treated in a non-standard, reversed sequence to find out. Dudas team expanded their research to include preclinical models for HCC in mice, after discovering that it was successful in 25 patients with HCC. He notes that the immune checkpoint blockade was first used to increase the immune system response. This enhanced the effectiveness and superiority of sorafenib (a standard multikinase inhibitor drug with anti–VEGFR) activity.
HCC is the second-most deadly form of cancer and is responsible for more that 700,000 deaths annually. It also happens to be the most common type of liver cancer. Around 15 years ago, Sorafenib emerged as the first systemic treatment for liver carcinoma. It works as an anti-VEGFR inhibitor to stop cancerous growth by targeting the new blood vessels that feed tumors and allow their progression. Programmed cell death 1 (PD1) antibodies, which are immune checkpoint inhibitors, restore the immune system’s ability to activate and kill cancer cells. Dudas’s lab discovered that immune checkpoint blockade can also reprogram the tumor microenvironment, resulting in greater T-cell activation and infiltration in HCC. This was in addition to being used with a multikinase inhibiter. This discovery prompted the MGH team and others to alter the sequence of the immune checkpoint inhibitor/multikinase inhibitor to test the effects on preclinical models.
Duda says that we found that sorafenib therapy is more effective when administered sequentially (meaning after anti-PD-1 treatment priming). We found that the CD8 cells were depleted, which negated the benefits of sorafenib. This confirms the feasibility of this approach.
Duda believes this new treatment strategy could be useful in other forms liver cancers, such as metastatic colorectal. Recently, a Japanese study demonstrated the effectiveness of immunotherapy and regorafenib. Duda states that, unlike chemotherapy which is focused on maximizing the tolerated dose, this approach uses the body’s immune systems to reprogram the tumor environment. This approach is promising in reducing the therapy doses and the toxicities that often accompany extended use of these drugs.
Duda is an associate professor at Harvard Medical School in Radiation Oncology. Hiroto K. Kikuchi, MD was a postdoctoral fellow in Radiation Oncology at MGH. He is currently a surgeon in Keio University in Japan. Aya Matsui (PhD) and Satoru Mrita (MD, PhD) are co-authors. Rakesh K. Jain (PhD), Andrew Werk Cook Professor of Radiation Oncology, Tumor Biology at Harvard Medical School, and director of Edwin L. Steele Laboratories to Tumor Biology at MGH is Rakesh K.Jain. Thomas Yau (MD), associate professor in Department of Medicine, Queen Mary Hospital University of Hong Kong provided clinical data supporting this approach.
Bayer HealthCare Pharmaceuticals Inc. supported the preclinical research under a sponsored agreement with Duda.
Reference: Kikuchi H, Matsui A, Morita S, et al. Infiltration of CD8+ T cells by multikinase inhibitors is increased in hepatocellular carcinoma patients with PD-1 blockade.. JNCI: 2022:djac051. doi: 10.1093/jnci/djac051
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