Targeting Latency Switch in EBV+ Lymphomas

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EBV-associated lymphomas are a heterogenous group of aggressive B-, T-, and NK- cell malignancies. In these lymphomas, EBV exists in a latent state where infectious virus is not produced but a limited number of viral proteins are expressed. One mechanism by which EBV+ lymphomas escape the immune response to EBV is through the latency I program where only the weakly immunogenic Epstein Barr nuclear antigen 1 (EBNA1) and non-coding RNAs are expressed. Latency I EBV+ lymphomas include Burkitt lymphoma and many cases of HIV-associated diffuse large B-cell lymphoma. Novel therapies are urgently needed in these subtypes where the outcome for patients with relapsed disease is dismal (OS<20% in Burkitt lymphoma, for example). In addition, many of the world’s cases arise in resource limited settings where upfront treatment with high dose chemotherapy is not feasible. Our approach to this unmet need in EBV+ lymphomas is to use epigenetic reprogramming to convert latency I tumors to the highly immunogenic latency II or III program, thereby rendering tumors sensitive to T-cell mediated killing. Using a high-throughput pharmacologic screen, we identified the hypomethylating agent decitabine as a potent inducer of latency II and latency III antigens in latency I EBV+ lymphomas. Furthermore, we observed that decitabine treatment in latency I tumors sensitizes resistant cells to killing by allogeneic EBV-specific T-cells, both in-vitro and in-vivo. Based on our preliminary findings, we hypothesize that epigenetic induction of latency switch in EBV+ lymphoma induces an anti-tumor immune response capable of eradicating disease through cytotoxic T-cell recognition of latency II/III viral epitopes. In the current proposal we will develop a rational approach to the use of epigenetic modulation to induce latency switching and immune mediated cell death in EBV+ lymphomas. We will determine which immune effector cells are required to eradicate latency switched EBV+ lymphomas including their activation status and function, and will characterize the predominant viral antigens to which they are responding. We will also explore mechanisms of potential resistance to decitabine mediated latency-switching and develop therapeutic combination strategies that maximize the percentage of cells that convert from latency I to latency II/III. Finally, we will establish therapeutic approaches that enhance the immune destruction of latency switched EBV+ lymphomas. Collectively, this proposal will accomplish the rational development of an entirely novel approach to the treatment of latency I EBV+ lymphomas, utilizing epigenetic reprogramming to induce immunogenic viral antigens in otherwise immunologically silent tumors. This work has implications beyond lymphomas to all EBV+ malignancies with restricted latency.