Handcuffing the culprit cancer: Immunotherapy for cold tumors with trispecific antibody

February 18, 2021

Several treatments for cancer have been devised by science, but unfortunately none of them are completely efficient or foolproof. Novel treatments with minimum side effects are one of the main aims of the ongoing cancer research. All research so far points to several therapy modes, of which immunotherapy, which prepares the body's own immune system to fight cancer, is a promising option. Bispecific antibodies (BsAbs) are synthetically made proteins that emerged as a promising second-generation immunotherapy. They engage with immune cells and enable them to target cancer in a specific manner.

Conventional use of T cells for this therapy has caused adverse effects in some cases. Moreover, they are ineffective against cold tumors, which are invisible to T cells of the immune system. This led to a search for other immune cells that could effectively target cold tumors with minimum adverse effects. Natural killer (NK) cells have therefore gained attention as prospective immunotherapy agents.

Now, a research team from China has designed a trispecific antibody that targets cancer cells and NK cells using anti-CD16, -IL15, and -CD19 domains. They call this molecule "161519 TriKE." As Dr. Zhigang Tian, one of the members of this research team and co-corresponding author of this study, explains, "Our intention was to attract CD19-positive tumor cells (such as the cells in Burkitt's lymphoma) to CD16-positive NK cells. IL15 can be used to maintain continuous division, development, and survival of NK cells, increasing their efficiency. Simply put, this protein acts like a handcuff, bringing cancer cells to killer immune cells. Additionally, these handcuffs have a trigger that keeps the killer cells active to destroy the cancer cells more efficiently."

In their study published in Cancer Biology & Medicine, the scientists used 161519 TriKE to target CD19-positive cancer cells in cell culture and measured the expression of markers that signify a successful immune response. They observed that several such markers increased in cells treated with 161519 TriKE. To test its preclinical efficiency, researchers developed "immune-reconstituted xenograft" mouse models, which are genetically engineered mice that constitute human peripheral blood mononuclear cells (PBMCs) and human tumors and tested to see if 161519 TriKE is able to initiate an immune response. 161519 TriKE was found to improve the interaction between NK cells and CD19-positive tumor cells. The team also found that 161519 TriKE is able to initiate a strong cytotoxic action of NK cells against tumor cells in cell culture. These results were same in live animals as well. Not only could 161519 TriKE successfully reduce tumor growth, it could also increase the overall survival of tumor-bearing mice.

So, what does this mean for cancer medicine? Prof. Haoyu Sun, co-corresponding author, explains the implications of their findings, "This study effectively provides a new method to develop immunotherapies against cancer. 161519 TriKE has the ability to transform research into application and shows potential for drug development. It can also be used in combination with other NK cell-based therapies."

The fundamental knowledge about the mechanism of action of this new molecule, 161519 TriKE, has the potential to revolutionize the current immunotherapy technology and can be redesigned to target other types of cancers.
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Reference

Authors: Ying Cheng (1,2), Xiaodong Zheng (1,2), Xuefu Wang (1,2), Yongyan Chen (1,2), Haiming Wei (1,2), Rui Sun (1,2), Zhigang Tian (1,2,3), Haoyu Sun (1,2)

Title of original paper: Trispecific killer engager 161519 enhances natural killer cell function and provides anti-tumor activity against CD19-positive cancers

Journal:Cancer Biology & Medicine

DOI: 10.20892/j.issn.2095-3941.2020.0399

Affiliations:

(1) Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China

(2) Institute of Immunology, University of Science and Technology of China, Hefei 230027, China

(3) Research Unit of NK Cell Study, Chinese Academy of Medical Sciences, Beijing 100864, China

About Dr. Zhigang Tian

Dr. Zhigang Tian is a professor at University of Science and Technology of China (USTC) in Hefei, China. He also serves as a Director of Institute of Immunology, Director of The CAS Key Lab of Innate Immunity and Chronic Diseases, and President of Medical Center at USTC, and is the former dean of School of Life Sciences. His research focuses on natural killer cells and immunotherapy associated with these cells, and he has published more than 300 papers in esteemed peer-reviewed journals.

About Dr. Haoyu Sun

Dr. Haoyu Sun is an associate professor at the University of Science and Technology of China (USTC) in Hefei, China. Her research focuses on natural killer cells and anti-tumor immunotherapies, and she has over 17 publications to her name.

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