Novel targeted therapies of T cell lymphomas

Abstract

T cell lymphomas (TCL) comprise a heterogeneous group of non-Hodgkin lymphomas (NHL) that often present at an advanced stage at the time of diagnosis and that most commonly have an aggressive clinical course. Treatment in the front-line setting is most often cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like regimens, which are effective in B cell lymphomas, but in TCL are associated with a high failure rate and frequent relapses. Furthermore, in contrast to B cell NHL, in which substantial clinical progress has been made with the introduction of monoclonal antibodies, no comparable advances have been seen in TCL. To change this situation and improve the prognosis in TCL, new gene-targeted therapies must be developed. This is now possible due to enormous progress that has been made in the last years in the understanding of the biology and molecular pathogenesis of TCL, which enables the implementation of the research findings in clinical practice. In this review, we present new therapies and current clinical and preclinical trials on targeted treatments for TCL using histone deacetylase inhibitors (HDACi), antibodies, chimeric antigen receptor T cells (CARTs), phosphatidylinositol 3-kinase inhibitors (PI3Ki), anaplastic lymphoma kinase inhibitors (ALKi), and antibiotics, used alone or in combinations. The recent clinical success of ALKi and conjugated anti-CD30 antibody (brentuximab-vedotin) suggests that novel therapies for TCL can significantly improve outcomes when properly targeted.

Efficacy and Treatment-Related Adverse Events of Romidepsin in PTCL Clinical Studies: A Systematic Review and Meta-Analysis

“…In several reports, a proportion of patients varying from 60 to 85% were treated with this strategy (3,32,33). The CHOP combination is effective in B cell lymphomas such as diffuse large B-cell lymphoma (DLBCL); however, its counterpart PTCL is associated with a poor prognosis; chemotherapy alone has resulted in median overall survival (OS) of 6.5 months due to rapid relapse (15,34).…”

Immunohistochemical evaluation and prognostic value of monocarboxylate transporter 1 (MCT1) and 4 (MCT4) in T-cell non-Hodgkin lymphoma

“…A variety of target-speci c treatments are undergoing clinical trials and are expected to help improve prognosis in patients with TCL. These interventions were designed based on the following mechanisms [33,34]: (1) Epigenetic regulation, mainly consisting of histone deacetylase inhibitors (HDACi), like Vorinostat, Belinostat, Romidepsin, Panobinostat, Chidamide, Quisinostat, and AR-42 [35]; (2) Antibody dependent cell-mediated cytotoxicity (ADCC), including technologies like Brentuximab vedotin (targeted CD30), Daratumumab (targeted CD38), Alemtuzumab (targeted CD52), IPH4102[36] (targeted KIR3DL2), TTI-621 [37] (targeted CD47), and AFM13[38] (targeted CD30/CD16A); (3) Cytotoxic reactions, involving chimeric antigen receptor T or NK (CAR-T/CAR-NK) cells with anti-CD7, anti-CD4, anti-CD5 or anti-TCR capabilities; (4) Signaling pathway blockers, including anaplastic lymphoma kinase (ALK) inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and microRNA (miR)-155 inhibitors [39]; (5) Other agents, such as E7777 [40] (an immunotoxin targeting the interleukin (IL)-2 receptor), Alisertib [41] (an inhibitor of Aurora A kinase (AAK)), and various antibiotics from Staphylococcus aureus [42] amongst others. However, to date, none of these technologies have produced a satisfactory outcome in patients with TCL, suggesting that further interventions are needed.…”

Genetic Landscape of Peripheral T-Cell Lymphoma

“…Alemtuzumab induces complement-mediated lysis and apoptosis in lymphoma cells and has been tested as a sole agent in clinical trials involving patients with heavily pretreated and refractory PTCL and MF/SS [ 57 ]. More recently, alemtuzumab is being tested in a clinical trial in combination with IL-15 in patients with relapsed ATLL [ 60 ].…”

“…Finding a suitable target antigen that the CARs can be directed to is challenging since most T-Cell associated antigens are the same for neoplastic and normal cells. In treatment for T-Cell lymphomas, chimeric antigen receptors have been engineered targeting CD7, CD4, CD5, CD30, and TCR [ 60 , 67 ]. Overall, the development of CAR-T therapy for mature T-Cell malignancies has been hampered by the absence of target antigens that are preferentially present on neoplastic T-Cells, and not on the normal counterpart cell.…”