Neoplasms originating from thymic T-cell progenitors and post-thymic mature T-cell subsets account for a minority of lymphoproliferative neoplasms. These T-cell derived neoplasms, while molecularly and genetically heterogeneous, exploit transcription factors and signaling pathways that are critically important in normal T-cell biology, including those implicated in antigen-, costimulatory-, and cytokine-receptor signaling. The transcription factor GATA-3 regulates the growth and proliferation of both immature and mature T cells and has recently been implicated in T-cell neoplasms, including the most common mature T-cell lymphoma observed in much of the Western world. Here we show that GATA-3 is a proto-oncogene across the spectrum of T-cell neoplasms, including those derived from T-cell progenitors and their mature progeny, and further define the transcriptional programs that are GATA-3 dependent, which include therapeutically targetable gene products. The discovery that p300-dependent acetylation regulates GATA-3 mediated transcription by attenuating DNA binding has novel therapeutic implications. As most patients afflicted with GATA-3 driven T-cell neoplasms will succumb to their disease within a few years of diagnosis, these findings suggest opportunities to improve outcomes for these patients.

B-cell non-Hodgkin’s lymphoma (NHL) refers to a heterogenous group of diseases, all of which have a wide range of treatment strategies and patient outcomes. There have been multiple novel, immune-based therapies approved in NHL in the last decade, including bispecific antibodies (BsAbs) and chimeric antigen receptor therapy (CAR-T). With a host of new therapies, an important next step will be determining how these therapies should be sequenced in contemporary management strategies. This review seeks to offer a framework for the ways in which BsABs can be incorporated into the current management paradigm for NHL, with special attention paid to diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL).

Relapsed/refractory non-Hodgkin lymphoma (r/r/NHL) is an aggressive disease with overall poor response rates to chemo-immunotherapy and autologous stem-cell transplant, especially in patients with diffuse large B-cell lymphoma. Major improvements in this disease space have come through the incorporation of novel immune therapies, including CD19/CD20 directed CAR-T cells and bispecific antibodies. These exciting new therapies continue to change the landscape of treatment for r/r NHL and have been incorporated in earlier lines of therapy with demonstrated efficacy and patient safety. In this review, the role of these treatments in the management of relapsed/refractory NHL is discussed in detail along with future directions of research.

There have been multiple approved agents for relapsed/refractory (r/r) Diffuse Large B-cell Lymphoma (DLBCL) over the last 8 years. The majority of these therapies act on specific signaling pathways in malignant B-cells. These signaling pathways stem from the B-cell receptor (BCR), Toll-Like Receptor (TLR), PI3K/AKT/mTOR, BCL-2, and XPO-1. In addition, novel therapies that target extracellular proteins (CD19, CD20, CD30, ROR1, and PD-1) have been developed. The purpose of this review is to discuss the various therapies that target these pathways and highlight the success and shortcomings of these novel agents.