Advances in Hodgkin Lymphoma Treatment: From Molecular Biology to Clinical Practice

Abstract

Classical Hodgkin Lymphoma (cHL) is a highly curable disease, but around 20% of patients experience progression or relapse after standard frontline chemotherapy regimens. Salvage regimens followed by autologous stem cell transplants represent the historical treatment approach for these cases. In the last decade, with the increasing understanding of cHL biology and tumor microenvironment role in disease course, novel molecules have been introduced in clinical practice, improving outcomes in the relapsed/refractory setting. The anti-CD30 antibody-drug conjugated brentuximab vedotin and PD-1/PD-L1 checkpoint inhibitors represent nowadays curative options for chemorefractory patients, and randomized trials recently demonstrated their efficacy in frontline immune-chemo-combined modalities. Several drugs able to modulate the patients' T-lymphocytes and NK cell activity are under development, as well as many anti-CD30 chimeric antigen receptor T-cell products. Multiple tumor aberrant epigenetic mechanisms are being investigated as targets for antineoplastic compounds such as histone deacetylase inhibitors and hypomethylating agents. Moreover, JAK2 inhibition combined with anti-PD1 blockade revealed a potential complementary therapeutic pathway in cHL. In this review, we will summarize recent findings on cHL biology and novel treatment options clinically available, as well as promising future perspectives in the field.

Keywords: CAR T-cells; Hodgkin Lymphoma; T-cell regulation; anti-CD30 drugs; epigenetic modulation; immune checkpoint inhibitors; immunochemotherapy.

Figure 1

PD1-mediated inhibition of T cell activity. Multiple signal transduction pathways converge in antigen-stimulated T lymphocytes to generate transcription factors that promote the expression of genes involved in activating and maintaining the T response. The main pathways involved are those of RAS/MAPK, PLCγ1 and PI3K/AKT. PD-1 activation results in SHP2-mediated dephosphorylation of CD3ζ, Zap-70, PKC, and PI3K and consequently with their inhibition.

Figure 2

Current target therapy approaches in cHL. 1: Brentuximab vedotin. 2: Nivolumab, pembrolizumab and other PD-1 inhibitors. 3: Camidanlumab tesirine. 4: Vibostolimab. 5: Favezelimab. 6: Magrolimab. 7: AFM13. 8: anti-CD30 CAR T-cells.