Combination therapy might improve outcomes in treatment-resistant liver cancer

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Researchers at Massachusetts General Hospital (MGH) have identified effective combination cancer therapies for refractory hepatocellular carcinoma (HCC) by suppressing tumor growth and increasing survival.In a treatise published in Journal for ImmunoTherapy of Cancer, Researchers have combined a multikinase inhibitor, regorafenib, to “reprogram” the tumor immune microenvironment, and combined with a programmed cell death 1 (PD1) antibody to stimulate anti-tumor immunity. Explain how the survival rates of mouse models of HCC have improved beyond each. Treatment should have been achieved alone.

“The holy cup of immunotherapy in the treatment of solid tumors like HCC is to attract cancer-fighting T cells into the tumor,” said Dan G., director of translational research at MGH’s GI Radiation Oncology. Duda, DMD, Ph.D. Explains. Senior author of the study. “We found that regorafenib delivered at the appropriate intermediate dose tricked cancer cells into expressing a chemokine known as CXCL10, which induces intratumoral T cell infiltration.”

HCC, the most common form of liver cancer, is an aggressive gastrointestinal disorder that is increasing globally by more than 3% annually. It is the second most deadly form of cancer and causes more than 700,000 deaths annually. The encouraging news for patients is the recent emergence of combination therapy with anti-vascular endothelial growth factor receptor (anti-VEGFR) inhibitors associated with blockade of the PD1 pathway.

This type of cancer develops a rich new vascular system that promotes tumor progression. This vascular system is very abnormal and limits the recruitment and activity of effector T cells. Anti-VEGFR inhibitors work to partially control the growth of tumors by normalizing the vascular system and increasing the infiltration of T cells into the tumor. This concept was first introduced by Dr. Rakesh K. Jain, director of the study’s co-author, Steele Laboratories for Tumor Biology, and a pioneer in the field of vascular biology and cancer treatment. PD1 inhibitors activate the immune system and kill cancer cells by inhibiting the interaction of the protein PD-L1 with the protein PD1 on the surface of some malignant and non-malignant cells in HCC. Restores ability. On the surface of T cells. This dual-treatment strategy has shown almost twice the response rate of 15% to 20%, which normally responds to anti-PD1 treatment alone, in several clinical trials in patients with HCC.

“Combination therapy has been a major step forward in this area, but despite the longevity, the fact that so many patients are experiencing recurrence makes it clear that treatment of liver cancer There are still limits, “said Jain. “We have suggested that inhibitors that can target multiple kinases beyond the VEGF receptor may be particularly effective in combating treatment resistance. Our research team Regorafenib normalizes blood vessels and chemokine CXCL10 in cancer cells. These intratumoral changes induce T cells to invade the tumor, where they can work more effectively. “

The results of the MGH study provide direct information for ongoing clinical trials of regorafenib in cancer patients. Indeed, the study is highly relevant to the future development of treatments for HCC and other cancers that metastasize to the liver, Duda said. “Our preclinical studies have shown the effectiveness of dual therapy, so we need to understand how to combine the ingredients in a way that maximizes patient benefit,” he says. “Our research has taken a major step in that direction by demonstrating the importance of targeting the immune microenvironment of HCC while using immunotherapy for this deadly cancer.”

Researchers open the door to the tumor microenvironment of CAR T cells

For more information:
Kohei Shigeta, Regorafenib in combination with PD1 blockade increases CD8T cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma. Journal for ImmunoTherapy of Cancer (2020). DOI: 10.1136 / jitc-2020-001435

Provided by Massachusetts General Hospital

Quote: Combination therapy is treatment-resistant liver cancer obtained on November 30, 2020 from https: // May improve outcomes (November 30, 2020)

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