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First-in-class immunotherapeutic agent could fuel the development of novel therapies for multiple types of cancer

Mar 22, 2021

wang-1 Xiang-Yang (Shawn) Wang, Ph.D.

The tumor microenvironment remains a major hurdle for the ultimate success of immuno-oncology due to its poorly immunogenic and highly immunosuppressive nature.

New research conducted by Xiang-Yang (Shawn) Wang, Ph.D., co-leader of the Developmental Therapeutics research program at VCU Massey Cancer Center and associate scientific director of immunology at the VCU Institute of Molecular Medicine, found that administering the immunotherapeutic agent Flagrp170 led to strong inhibition of multiple malignancies in preclinical models, including head and neck squamous cell carcinoma, melanoma and breast cancer, without evident tissue toxicities.

“These findings support a potential use of Flagrp170 to re-shape the tumor environment to effectively and safely mount antitumor immune responses,” said Wang, who is also the Harry and Judy Wason Chair in Cancer Research at Massey and a professor in the Department of Human and Molecular Genetics at the VCU School of Medicine. “This immunostimulatory agent may also be used in combination with other conventional cancer treatment modalities to improve overall outcomes.”

The study, recently published in the Journal for ImmunoTherapy of Cancer 2021, found that directly administering Flagrp170 into the tumor, a process known as in situ viral-immunotherapy, induced a distinct set of cytokines or cell signalling molecules that aid in immune responses.

Cytokines are essential for generating and maintaining antitumor immunity, signified by increased tumor-infiltrating immune cells capable of killing cancer cells. Study findings suggest that Flagrp170 may be used to reprogram immunologically cold cancers, which are often resistant to cancer therapies.

Flagrp170 is a first-in-class multifunctional immune modulator engineered by Wang’s team. “This agent is created by engineering an immunostimulatory microbial-derived signal into a protein molecule called ‘chaperone’ that is known to carry and deliver immunological targets of cancer cells,” said Wang. “This idea was also inspired by the work of Dr. William Coley, a prominent surgeon and the father of modern cancer immunotherapy who made the first attempt to treat patients by administering live bacteria called Coley’s toxins in the 1890s. Such a molecular design allows efficient capturing and presenting of tumor antigenic targets to the immune system and associated delivery of immunostimulatory signals that are essential for activation of T-cells, which are a type of immune system cell.”

Wang evaluated the immunostimulatory activity, antitumor potency and potential side effects of Flagrp170 by using a replication impaired adenovirus, which is a common virus that causes a range of illnesses and symptoms such as colds, sore throat, fever and cough. Antibody neutralization and mice deficient in pattern recognition receptors – proteins capable of recognizing molecules frequently found in pathogens -- were also utilized to evaluate the immunological mechanism of Flagrp170.

Results showed a novel immune-potentiating activity of Flagrp170 via engaging the innate pattern recognition receptor NLRC4 to bridge and orchestrate the different arms of the immune system, supporting its potential clinical use to transform the immunosuppressive tumor environment to restore and strengthen the antitumor functions of immune cells.

“These results provide new insights into the immunotherapeutic activity of Flagrp170 by identifying a type of cytoplasmic pattern recognition receptor – a protein capable of recognizing molecules frequently found in pathogens – called NLRC4. This receptor is responsible for the Flagrp170-mediated antitumor immune responses,” said Wang.

Wang will continue working with Massey researchers and the National Cancer Institute to explore clinical translation of Flagrp170 and its potential to be an effective immunotherapeutic agent.

In addition to Wang, this study was co-authored by Chunqing Guo, Ph.D., member of the Developmental Therapeutics research program at VCU Massey Cancer Center and assistant professor in the VCU Department of Human and Molecular Genetics. Additional contributors include Joseph W. Landry, Ph.D., associate professor in the Department of Human and Molecular Genetics and member of Massey’s Cancer Biology research program; Andrew S. Poklepovic, M.D., and Harry D. Bear, M.D., Ph.D., members of Massey’s Developmental Therapeutics research program, and John R. Subjeck, Ph.D., and Elizabeth A. Repasky, Ph.D., of Roswell Park Comprehensive Cancer Center.

This work was supported in part by award W81XWH-11-0481 from the Department of Defense and awards CA099326, CA154708 and CA175033 from the National Cancer Institute. Services in support of the research project were provided by the VCU Massey Cancer Center Flow Cytometry Core and supported, in part, with funding from NIH-NCI Cancer Center Support Grant P30 CA016059.

Written by: Melissa Mitchell

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