Promising drugs and treatment options for pediatric and adolescent patients with Hodgkin lymphoma

Abstract

Currently-available therapies for newly-diagnosed pediatric and adolescent patients with Hodgkin lymphoma result in >95% survival at 5 years. Long-term survivors may suffer from long-term treatment-related side effects, however, so the past 20 years have seen clinical trials for children and adolescents with HL gradually abandon the regimens used in adults in an effort to improve this situation. Narrower-field radiotherapy can reduce long-term toxicity while maintaining good tumor control. Various risk-adapted chemo-radiotherapy strategies have been used. Early assessment of tumor response with interim positron emission tomography and/or measuring metabolic tumor volume has been used both to limit RT in patients with favorable characteristics and to adopt more aggressive therapies in patients with a poor response. Most classical Hodgkin's lymphoma relapses occur within 3 years of initial treatment, while relapses occurring 5 years or more after diagnosis are rare. As the outcome for patients with relapsed/refractory classical Hodgkin lymphoma remains unsatisfactory, new drugs have been proposed for its prevention or treatment. This review summarizes the important advances made in recent years in the management of pediatric and adolescent with classical Hodgkin lymphoma, and the novel targeted treatments for relapsed and refractory classical Hodgkin lymphoma.

Keywords: Epstein-Barr virus; Hodgkin lymphoma; adolescent; chemotherapy; radiation; tumor target.

FIGURE 1

A model for the cellular germinal center origin of HRS cells. The origin of HRS cells has long been a matter of debate. Since the detection of clonal rearrangements of the immunoglobulin V gene in isolated HRS cells, it is now accepted that clonal B lymphocytes originate from HRS cells, with only a small proportion deriving from T lymphocytes. That said, HRS cells lose B-cell-specific genes (e.g., immunoglobulin genes and genes involved in the antigen presentation by MHC) and show characteristic positivity for nuclear paired box protein 5 (PAX5) (Khan et al., 2018) and CD30 antigen (Swerdlow et al., 2016; Weniger et al., 2018). PAX5 encodes a B-cell specific activator protein, a transcription factor expressed in the early but not in the late stages of B-cell differentiation. B-cell activation leads to the expression of the membrane receptor CD30, which regulates the apoptotic NF-kB pathway, and thus controls the load of the B-cell population (Küppers, 2009), B-cell receptor; dim, moderate expression; Hodgkin cells (H cells) of nodular lymphocyte-predominant HL; Ig, immunoglobulins; Reed-Sternberg (RS) cells of cHL.

FIGURE 2

Loss of MHC class I (A) and class II (B) expression and MHC antigen presentation (A) A CD8⁺ cytotoxic T cell targets a cell expressing MHC-I/antigen complex after intracellular proteins have been digested by the proteasome into small peptides in Hodgkin and Reed-Sternberg cells, but the surface expression of the MHC-I/peptide complex is reduced due to transporters of peptides like processing (TAP) carriers and the beta 2 microglobulin (β2m) chain. Both the induction of apoptosis and the release of granzyme/perforin by CD8-T cells are consequently inhibited. In normal conditions, the peptides translocate into the endoplasmic reticulum (ER), allowing the antigen to bind to MHC-I. Then, after a passage in the Golgi structure and packaging in secretory vesicles, the MHC-I/peptide complex is fused with the plasma membrane and exposed to the surface of the target cell. The CD8⁺ T cell that recognizes and binds the MHC-I/peptide complex through its specific T-cell receptor (TCR) can induce the death of the target cell by activating the classical apoptotic signaling (Fas/caspase) pathway together with the release of the cytotoxic granzyme B and perforin from T-cell granules. In the case of tumor cells infected by EBV, the EBV BNLF2a, BGLF5, and BILF1 proteins produced during viral replication reduce the expression of MHC-I -antigen complexes, and thus contribute to the CD8⁺ T cell immune escape of the infected cells. (B) Direct and indirect killing of target cells by CD4⁺ T cells. MHC-II alpha and beta chains are normally assembled in the endoplasmic reticulum (ER). MHC-II binds the human leukocyte antigen DM (HLA-DM) to protect itself from endosomal degradation. HLA-DM releases the class II-associated invariant chain peptide (CLIP), replacing it with a sequence-specific peptide. The complex MHC-II/peptide (pMHC-II) goes to the cell surface, where MHC-II can present the peptide to the CD4⁺ T-cells. After the recognition of pMHC-II through its T-cell receptor (TCR), the CD4⁺ T-cell may kill the target cell directly by contact, or indirectly through the mediation of macrophages. Most HRS cells lack the HLA-DM, so the MHC-II is unprotected or unable to exchange the CLIP molecule with the antigenic peptide, and this leads to the absence of pMHC-II expression and a reduced tumor cell killing by CD4⁺ T-cells. The absence of pMHC-II expression is known to occur in about 40% of patients with cHL, and it is associated with poor treatment outcomes (Roemer et al., 2018). In other situations, HRS cells use pMHC-II to engage the immune suppressor lymphocyte-activation gene-3 (LAG3) receptor present on T cells, NK cells, plasmacytoid dendritic cells, and macrophages (Maruhashi et al., 2018; Triebel et al., 1990) in order to avoid immune recognition and exhaust cytotoxic T and NK cells. LAG-3 cooperates closely with PD-1 to alter regulator T cell homeostasis in cHL (Michot et al., 2021). Interestingly, CD4⁺ LAG3⁺ T cells have been found close to pMHC⁺ HRS cells, indicating that they play an important role in the development of the characteristic permissive microenvironment in cHL.

FIGURE 3

CAR-T structure and CAR-T cell therapy. The antigen-binding domain confers target specificity to CAR-T cells. This domain generally consists of variable heavy and light chains of monoclonal antibodies bound by a linker to form a single-chain variable fragment (scFv). The extracellular domain dictates the affinity and efficacy of the CAR-T cells and is independent of MHC-mediated antigen presentation. The difference in the intracellular co-stimulatory domains results in the modulation of different pathways like T cell differentiation and type of cell death. CAR-T treatment works by redirecting a patient’s own immune T cells, engineered in the laboratory, to directly identify and attack cancer cells.