Investigational Therapy TAK-659 Targets Lymphomas Linked to Epstein-Barr Virus, Mouse Study Shows

Investigational Therapy TAK-659 Targets Lymphomas Linked to Epstein-Barr Virus, Mouse Study Shows

TAK-659, an investigational compound being developed by Takeda Pharmaceuticals, is able to target lymphomas associated with Epstein-Barr virus (EBV) infection, preventing their growth and spread, a mouse study shows.

The study, “Spleen Tyrosine Kinase Inhibitor TAK-659 Prevents Splenomegaly and Tumor Development in a Murine Model of Epstein-Barr Virus-Associated Lymphoma,” was published in mSphere.

EBV infection is extremely common — estimated to affect up to 95% of the world population. The infection can cause mononucleosis, also known as “kissing disease,” but in some cases, infected people do not experience any symptoms at all during their lives.

Although EBV does not directly cause cancer, previous studies reported that EBV infection increases the risk of some types of cancers, including Hodgkin’s lymphoma, Burkitt’s lymphomanasopharyngeal carcinoma, and stomach cancer.

One of the reasons why scientists believe EBV infection increases patients’ susceptibility to lymphoma has to do with its effect on promoting the growth of B-cells — a type of memory immune cell that produces antibodies and directs killer T-cells toward a specific threat.

This effect is caused by one of the two types of viral proteins produced by EBV, known as latent membrane protein 2A (LMP2A), which is able to hijack and manipulate components of the B-cells’ machinery to extend their survival and proliferation.

One of these components is spleen tyrosine kinase (SYK), an enzyme involved in the control of cell survival and proliferation whose deregulation has been linked to multiple types of malignancies, such as lymphoma, leukemia, and breast cancer.

TAK-659, an investigational therapy that works by inhibiting SYK activation and preventing excessive cell growth, is currently being tested in clinical trials (NCT02000934, NCT02323113, NCT02834247, and NCT02954406) to assess its potential for the treatment of lymphoma and other types of solid tumors.

Preliminary data from these studies have already demonstrated that TAK-659 is nontoxic and highly effective against particular subtypes of lymphomas.

In this study, microbiologist Richard Longnecker, PhD, from the Northwestern University Feinberg School of Medicine in Chicago, and collaborators analyzed the effects of TAK-659 on mice genetically engineered to express LMP2A in B-cells to induce lymphoma development.

TAK-659 was able to successfully prevent tumor growth by promoting cancer cell death and preventing metastases in the bone marrow of treated mice. Moreover, the treatment was able to specifically target and destroy cancer cells, while leaving EBV-infected, but otherwise healthy, spleen cells unharmed.

“Our data demonstrate the potential of TAK-659 in devising treatment strategies for EBV-positive and EBV-negative hematologic malignancies,” the investigators wrote.

Based on these preclinical findings, which validated the therapy’s effectiveness in EBV-associated lymphomas, Takeda has decided to include a group of EBV-positive patients in one of the ongoing Phase 1 trials currently assessing its clinical effectiveness in lymphoma patients.

“The drug has promise both as a single agent and in combination with other cancer therapies, including immunotherapies,” Karuppiah Kannan, global program leader for Takeda in Cambridge, Massachusetts, said in a press release. “The findings published … show how good preclinical data can push research faster toward something that will help patients. It’s an example of how bench to bedside happens. Now the clinical data has to take us to the next step.”

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