Novel Targets and Therapies in T Cell Lymphoma

Abstract

This review presents the recent advances in our understanding of the cellular pathogenesis of T cell non-Hodgkin lymphoma (NHL) and the potential of clinically targeted therapies. Patients with T cell NHL continue to face a limited prognosis, with the large majority experiencing a relapsed/refractory disease course and succumbing to their disease. Recent significant advances in our understanding of lymphomagenesis have not only revealed the complexity of T cell NHL but also helped to identify the cellular structures and pathways required for tumour proliferation, immune evasion, and therapy resistance. The NFκB pathway plays a critical role in T cell lymphoma through complex interactions with cell surface receptors and ligands, the proteasome, and crosstalk with ancillary pathways, such as the PI3K/Akt/mTOR cascade, which are also involved in chemokine and cytokine-mediated cellular signalling and growth. There is now also growing evidence for recurrent mutations involving the JAK/STAT pathway in a number of T cell lymphoma subtypes. Preclinical studies have highlighted the importance of novel cell surface proteins, downstream pathways, proteasome activation of NFκB, nuclear transport proteins, folate metabolism, epigenetic regulators, and cell of origin derivation. These advances represent a new era in T cell NHL therapy development. Although the optimal chemoimmunotherapy combination for first-line and salvage therapy is yet to be defined, the future paradigm is clearly shifting towards a biology-driven approach, which will hopefully yield improved outcomes for all patients with T cell lymphoma.