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).	Immunomodulatory agents: Lenalidomide + anti-PD-1 mAbs (NCT02875067, NCT03015896, NCT01953692) Ibrutinib + anti-PD-1 mAbs (NCT02940301).
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].