Epigenetic Modifying Agents Sensitize EBV+ Lymphomas to Immunotherapy

Background & Unmet Need

• The Epstein-Barr virus (EBV) is one of the most common human viruses and is associated with the development of a number of lymphomas, such as Burkitt’s lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and Hodgkin’s lymphoma
• EBV has a strong propensity to remain latent, and can be classified into different latency patterns based on expression of immunogenic EBV proteins
• Most EBV-driven lymphomas express the latency I program, in which the single EB nuclear antigen (EBNA1) is produced which allows tumors to evade immune responses
• A minority of EBV-driven lymphomas display the highly immunogenic latency II/II program, which is responsive to common immunotherapies
• Unmet Need: There is an urgent need for methods to transform EBV-driven lymphomas to make them more amenable to immunotherapy treatment

Technology Overview

• The Technology: Use of epigenetic modifying agents to convert treatment-resistant latency I lymphomas into immunotherapy-responsive latency II/III lymphomas
• The Discovery: A high throughput screen with follow-up tests was used to identify the hypomethylating agents decitabine and 5-azacytidine as potent inducers of immunogenic EBV proteins (Figure 1)
• Decitabine treatment of latency I BL cells in vitro sensitized them to lysis by EBV-specific cytotoxic T-cells (EBV-CTLs; Figure 2A)
• PoC Data: Decitabine treatment of mice with latency I BL xenografts followed by EBV-CTLs resulted in T-cells effectively targeting and inhibiting tumor growth (Figure 2B)
• Combination treatment method is applicable to additional modes of immunotherapy (e.g., CAR-T, checkpoint inhibitors)

Technology Applications

• Treatment of EBV+ latency I lymphomas with a combination of epigenetic modifying agents and an immunotherapy (e.g., EBV-CTLs, CAR-T cells, and checkpoint inhibitors)
• Technology is also potentially useful for treating nasopharyngeal and gastric cancers

Technology Advantages

• Induction of immunogenic antigens by epigenetic modifying agents occurs at low doses and persists long after agent removal
• In addition to DCB and 5-Aza, the technology also provides a screening method for discovering additional molecules that alter EBV latency