Newly Emerging Therapies Targeting Viral-Related Lymphomas

Abstract

Gamma-(γ)-herpes virus lymphomas comprise a heterogenous group of B-cell and T-cell neoplasms most commonly associated with Epstein Barr virus (EBV) and rarely human herpes virus-8 (HHV-8) infection. Adult T-cell leukemia/lymphoma (ATLL) is a unique disease entity caused by the human T-cell lymphotrophic virus, type 1 (HTLV-I), the only retrovirus known to cause cancer in humans. Viral lymphomas behave aggressively and disproportionally affect immunocompromised individuals and those living in underdeveloped regions. These diseases are often difficult to treat with conventional approaches. Despite recent advancements using cytotoxic, lymphoma-specific, and adoptive therapies, the long-term outcome of patients with γ-herpesvirus lymphomas occurring in severely immunocompromised patients and ATLL continues to be poor. Lytic-inducing therapies targeting NF-κB, and viral and tumor cell epigenetic mechanisms afford the advantage of exploiting the intrinsic presence of oncogenic viruses to eradicate infected tumor cells. In this review, viral-related lymphomas and newly emerging clinical approaches targeting viral latency are discussed.

Suppression of T cell responses in the tumor microenvironment

“…In addition, novel, non-self tumor-specific antigens are created by gene fusions such as occurs in chromosome translocations, for example BCR-ABL1 [6], or are expressed in tumors of viral origin [7,8]. Finally, several antigens have been identified that are products of aberrant translation or splicing in tumors such that novel epitopes are generated from normally non-translated regions of mRNA [9,10], created by ribosomal frameshifting [11], or expressed from introns that fail to be spliced from the mature transcript [12][13][14][15].…”

Epstein-barr virus infected gastric adenocarcinoma expresses latent and lytic viral transcripts and has a distinct human gene expression profile

“…Emerging targeted therapy makes it all the more important to identify infected cancers and to characterize biochemical defects such as ERBB2 overexpression that increases likelihood of response to trastuzumab in metastatic gastric cancer patients [16-18]. EBV-infected compared to uninfected gastric cancer has a favorable prognosis [19], and clinical trials are beginning to explore virus-targeted therapy such as 1) infused EBV-specific cytotoxic T cells or NK cells [20-23], 2) reversing the EBV-related methylator phenotype [24], 3) triggering lytic viral replication that could then incite the body’s innate and adaptive immune responses to kill infected tumor cells [25-33], and 4) lytic induction therapy co-administered with antiviral nucleoside analog such as gancyclovir that is phosphorylated and thus activated by viral kinases promoting cytotoxicity [34-41].…”

Novel Treatments of Adult T Cell Leukemia Lymphoma

“…Vorinostat induced 30% response rates (Olsen et al, 2007), while Romidepsin induced 34% response rates (Whittaker et al, 2010). Combining valproic acid, a first generation HDACI, with AZT/IFN as a maintenance therapy was tested in 13 ATL patients (Ramos and Lossos, 2011).…”