A new treatment strategy for hepatocellular carcinoma (HCC) that first primes the tumor with an immuno checkpoint inhibitor and then uses a multikinase inhibitor drug was found to be very promising for treating the deadly disease. This was revealed in a Massachusetts General Hospital study. In a Paper published in Journal of the National Cancer InstituteResearchers reported that the new sequence approach improved the effectiveness of dual drug therapy. This could allow for de-escalation of prolonged use of medication and reduce toxic drug exposure.
The traditional way to test new treatments for HCC patients was to use a combination of a multikinase inhibitor and immune checkpoint blockade. Dan G. Duda (DMD), PhD, is the director of translational research at MGH in GI Radiation Oncology and the senior author of the study. However, no one knew what the effects of changing the sequence of these therapies might have.
Duda conducted a retrospective analysis on patients who were treated in a non-standard, reversed sequence to find out. Dudas team began to investigate preclinical models of HCC in mice after learning that it had positive outcomes in a group of 25 HCC patients. 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. It is responsible for more than 700,000. deaths each year worldwide. It is also the most common form liver cancer. Around 15 years ago, Sorafenib was the first systemic treatment of liver cancer. It is an anti-VEGFR inhibiter and works to control cancerous cell growth by targeting new blood vessels which feed the tumor and allow its advancement. Programed cell death 1- (PD1) antibodies are an immune checkpoint inhibitor that restores the immune system’s ability activated and kills cancer cells. Dudas lab discovered last year that immune checkpoint blocking can also be used to reprogram tumor vascular microenvironments, which results in increased T-cell infiltration and activation of HCC cells when combined with a multikinase inhibition. That discovery was what prompted the MGH team’s decision to change the sequencing of the multikinase inhibitor and immune checkpoint inhibit to see what would happen in clinical models.
Duda says that we found that sorafenib therapy is more effective when administered sequentially (meaning after anti-PD-1 treatment priming). This approach is feasible, as we found that the CD8 T cell count was depleted in this model.
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 says that unlike chemotherapy, which is designed to use the maximum tolerated dose, the new treatment strategy uses the body’s immune system to reprogram tumor environments. 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 of Radiation Oncology in Harvard Medical School. Hiroto Kikuchi (MD), was a postdoctoral fellow at MGH in the Department of Radiation Oncology. He is currently a surgeon at Keio University, 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. sponsored the preclinical study under a research 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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