Immune Checkpoint Inhibition in Classical Hodgkin Lymphoma: From Early Achievements towards New Perspectives
Table 1
Summary of immune escape mechanisms in cHL and alternative therapeutic strategies in development.
Immune escape mechanisms in cHL
Therapeutic agents with immunomodulatory properties tested in recruiting/active clinical trials in R/R cHL
Downregulation of MHC class I and II expression
Epigenetic modifiers in combination with immune checkpoint inhibitors∗: Decitabine + anti-PD-1 mAbs (NCT03250962)
Surface PD-L1/2 overexpression
JAK/STAT inhibitors in combination with immune checkpoint inhibitors: Ruxolitinib + anti-PD-1 mAbs (NCT03681561) Combinatorial immune checkpoint blockade: Ipilimumab + Nivolumab (NCT02408861, NCT02304458) Anti-LAG3 mAb (MK-4280) + anti-PD-1 mAb (NCT03598608) Brentuximab + Nivolumab +/- Ipilimumab (NCT01896999)
CTL anergy through PD-1-PD-L1/2 interaction (HRS / TAM).
Adoptive cell therapy: Chimeric Antigen Receptor (CAR) CD30-targeting T-cells (NCT01316146, NCT01192464, NCT02690545, NCT02917083, NCT02259556, NCT03602157, NCT03049449) Bi-specific chimeric antibody constructs: INBRX-105 (PD-L1-CD137) provides a combination of PD-L1 blockade with concomitant T-cell co-stimulation through CD137 (4-1BB) agonism (NCT03809624)
NK cell inhibition mediated by TGF-ß and NKG2D-L interaction (HRS / MSC).
Bi-specific chimeric antibody constructs: AFM13 (CD30-CD16A) recruits NK cells via binding to CD16A as immune effector cells (NCT02321592) AFM13 + anti-PD-1 mAbs (NCT02665650)
CTL inhibition through TGF-ß, IL-10, Gal-1, TIMP1 and PGE2. Stimulation of CD4 T-cells differentiation towards Treg and Th2 phenotype through TGF-ß, IL-10, Gal-1, TIMP1 and PGE2. Chemo attraction of Treg and Th2 through CCL5 (fibroblasts), CCL17 and CC22 (HRS).
Th1 and CTL enhanced apoptosis through Fas ligand surface expression (HRS).
Induction of immunogenic cell death (ICD) of tumor cells with chemotherapy in combination with immune checkpoint inhibitors: Bendamustine + anti-PD-1 mAbs (NCT03343652) Bendamustine + Gemcitabine + anti-PD-1 mAbs (NCT03739619)
∗It should be noted that the trials involving inhibitors of deacetylase (HDACi) in cHL revealed a limited efficacy with significant hematological and electrolytic toxicities, rendering their future development difficult in the absence of predictive biomarkers [89, 90].
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