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Combined therapy makes headway for liver cancer

Adding another drug to immunotherapy increased response rate for hepatocellular carcinoma patients in phase 2 trial, UTSW reports

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DALLAS – May 02, 2024 – A drug that targets a protein known as phosphatidylserine boosted the response rate for hepatocellular carcinoma (HCC) patients receiving immunotherapy without compromising their safety, according to results of a phase two clinical trial conducted by UT Southwestern Medical Center. The findings, published in Nature Communications, show the potential benefits of augmenting immunotherapy for this and other forms of cancer.

David Hsieh, M.D.
David Hsieh, M.D., is Assistant Professor of Internal Medicine in the Division of Hematology and Oncology and a member of the Experimental Therapeutics Research Program of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

“This study shows the promise of improving the success of cancer immunotherapies by targeting other immunomodulating proteins simultaneously,” said study leader David Hsieh, M.D., Assistant Professor of Internal Medicine in the Division of Hematology and Oncology and a member of the Experimental Therapeutics Research Program of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

HCC is the most common form of liver cancer and the fourth most frequent cause of cancer-related deaths worldwide. For many years, the only existing treatment for tumors of this kind that can’t be surgically removed was a drug called sorafenib. It works by slowing the growth of tumor-feeding blood vessels. Although this targeted therapy drug was groundbreaking when it was approved by the U.S. Food and Drug Administration in 2007, it extends survival by only a few months.

More recently, immunotherapies – treatments that spur the immune system to fight tumors – have emerged as the most effective treatments for HCC patients. However, only a fraction of patients responded to these drugs when delivered alone, and combining multiple immunotherapies increased the likelihood of serious and occasionally deadly side effects.

Several years ago, researchers discovered that phosphatidylserine, a fatty substance called a phospholipid sometimes present on the surface of cancer cells, appeared to interact with immune cells to prevent them from attacking tumors. An antibody drug called bavituximab that neutralizes phosphatidylserine showed no effect on tumor response, progression, or survival when administered alone across multiple cancer types or when combined with sorafenib in HCC. But bavituximab had never been tested in combination with immunotherapy agents.

Toward that end, Dr. Hsieh and his colleagues recruited 28 patients with HCC receiving care at UT Southwestern and Parkland Health. These patients, whose cancers couldn’t be surgically removed, received imaging of their tumors at the start of the study. They then received a combination of bavituximab and pembrolizumab, an immunotherapy drug approved in 2016 to treat various cancers. While receiving both therapies, these patients had periodic imaging to determine whether their tumors shrank, stopped growing, or continued to grow and multiply. The researchers followed these patients for an average of 28.5 months.

Although previous clinical trials had shown that only about 16% of HCC patients responded to pembrolizumab alone, nine patients, or 32%, responded to the combined therapy. Two of them had a complete response, with no evidence of disease on imaging at the end of the trial. The combined therapy halted progression in another 32% of patients. For responders, the two drugs continued to shrink their tumors for a median time of 13.3 months, and four patients were still responding to the combination therapy when the study ended.

Researchers noted that adding bavituximab did not appear to increase side effects over those taking pembrolizumab alone based on data from prior trials – an important point showcasing this combination’s safety.

These results suggest that adding agents that target phosphatidylserine to immunotherapy regimens could increase the likelihood of response in HCC and potentially other cancers in which this protein might affect anti-cancer immunity.

Other UTSW researchers who contributed to this study include co-first author Muhammad S. Beg, M.D., Adjunct Associate Professor of Internal Medicine; Radhika Kainthla, M.D., Assistant Professor of Internal Medicine; Jay Lohrey, M.D., Assistant Professor of Internal Medicine and Medical Director of the Simmons Cancer Center located at the Moncrief Cancer Institute in Fort Worth; Syed M. Kazmi, M.D., Associate Professor of Internal Medicine; Anil K. Pillai, M.D., Professor of Radiology and Chief of Vascular Interventional Radiology; Rolf Brekken, Ph.D., Professor of Surgery and Pharmacology and in the Hamon Center for Therapeutic Oncology Research; Chul Ahn, Ph.D., Professor in the Peter O’Donnell Jr. School of Public Health and Director of the Biostatistics Shared Resource in the Simmons Cancer Center; Amit G. Singal, M.D., M.S., Professor of Internal Medicine and in the O’Donnell School of Public Health, Medical Director of the Liver Tumor Program, and Chief of Hepatology; Hao Zhu, M.D., Professor in the Children’s Medical Center Research Institute at UT Southwestern (CRI) as well as in Internal Medicine and Pediatrics, co-leader of the Development and Cancer Research Program in the Simmons Cancer Center, and Director of the CRI Tissue Regeneration Program; Yujin Hoshida, M.D., Ph.D., Professor of Internal Medicine and Director of Liver Tumor Translational Research; Adam C. Yopp, M.D., Professor of Surgery, Chief of the Division of Surgical Oncology, and Surgical Director of the Liver Tumor Program; Leticia Khosama, M.S.N., Advanced Practice Registered Nurse; Mary Claire Maxwell, M.S.N., Advanced Practice Registered Nurse; Heather Kline, M.S., Advanced Practice Registered Nurse; Courtney Katz, M.S., Research Associate; and Ellen Siglinsky, B.S., Clinical Research Manager.

Dr. Brekken is an Effie Marie Cain Research Scholar. Dr. Hoshida holds the H. Ray and Paula Calvert Chair in Gastroenterology Oncology in Honor of Udit Verma, M.D. Dr. Kazmi is a Eugene P. Frenkel, M.D. Scholar in Clinical Medicine. Dr. Singal is a Dedman Family Scholar in Clinical Care and holds the Willis C. Maddrey, M.D. Distinguished Chair in Liver Disease. Dr. Yopp holds The Occidental Chemical Chair in Cancer Research. Dr. Zhu holds the Nancy B. and Jake L. Hamon Distinguished Chair in Therapeutic Oncology Research.

Drs. Ahn, Brekken, Hoshida, Hsieh, Kazmi, Singal, Yopp, and Zhu are all members of the Simmons Cancer Center.

For this study, Merck provided funding along with pembrolizumab while OncXerna Therapeutics supplied bavituximab. Dr. Hoshida is supported by grants from the National Cancer Institute (CA233794, CA255621), the European Commission (ERC-AdG-2020-101021417), and the Cancer Prevention and Research Institute of Texas (RR180016). This study was also supported by the National Cancer Institute (NCI) Cancer Center Support Grant (P30CA142543).

Author financial disclosures can be found in the manuscript.

About UT Southwestern Medical Center  

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.