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Hjalgrim et al. J Transl Genet Genom 2022;6:134-46 https://dx.doi.org/10.20517/jtgg.2021.46 Page 142

This communication between the HRS cells and the TME can be interfered with by antibodies blocking the
interaction between PD-1 and PD-L1 and PD-L2, respectively. Two such compounds directed against PD1,
Nivolumab and Pembrolizumab, in single-agent trials in relapsing and refractory cHL have produced
[5]
overall response rates in the range of 54%-87%, but less impressive complete response rates (< 30%) .

Consequently, these drugs are now evaluated in combination with other treatments both as first-line
treatment and for patients with relapsing or refractory disease [5,41] . Here, the combination of Nivolumab
with brentuximab vedotin for relapsing or refractory cHL was recently reported to result in objective and
[76]
complete response rates of 85% and 67%, respectively after a median follow-up of nearly three years .
The mechanisms by which PD-L1/L2 blockers induce tumour regression are still poorly understood. E.g., in
one study HRS cells seemed to disappear almost instantaneously upon Nivolumab treatment initiation
accompanied by decreased numbers of Type-1 regulatory T-cells and PD-L1-positive macrophages but not
[77]
by clonal CD8-positive cytotoxic T-cell expansion . Possibly the effects of Nivolumab treatment is in part
mediated through newly recruited CD4-positive T-cell clones that are themselves cytotoxic and/or interact
with innate immune cells, especially NK cells, which may correlate with treatment outcome . Indeed, there
[78]
is an increasing interest in understanding how HRS cells circumvent being culled by NK cells because of
their loss of HLA class I [58,75,79,80] and in attempting to modulate/activate the innate immune response to treat
cHL [81,82] .

Theoretically treatment with PD-1 blockers [12,72] should result in better outcomes for EBV-positive cHLs
than for EBV-negative cHLs; however, this cannot be determined based on currently reported studies,
which also further details the rationale for these treatment proposals [5,83] .

CONCLUSIONS
Epidemiologic studies have long suggested that EBV-positive and EBV-negative cHL are aetiologically
different. With standard chemo- and radiotherapy for cHL the clinical relevance of this causal heterogeneity
has been questionable. However, with modern modalities targeting HRS cell characteristics and
determinants of TME, cHL aetiology may become important.

We have provided a simplified picture of this possibility but emphasize that there are other pathways and
mechanisms as well that may be relevant for aetiology-specific cHL treatment. The TME is very dynamic
and interacting with treatment regimens as well. Therefore, one cannot truly assess the efficacy of a certain
combination of risk stratification algorithms and treatment modalities without conducting a large
randomized trial designed for that purpose.

The introduction of T-cell therapy and immune checkpoint blockade into clinical practice in our view
should motivate renewed ambitious efforts in developing proposals for risk stratification that at the outset
aim at utilizing existing information, including histology and EBV-status, more comprehensively by
applying modern statistical methods on all the available well-curated data. In all likelihood, the new
treatment modalities described above and the underlying risk stratification schemes will turn out to be
progress in HL treatment. Nevertheless it may be possible to do even better by using aetiological
information more comprehensively in the risk stratification and treatment allocation, possibly at the
minimal cost of introducing computer-assisted treatment allocation instead of the old simple and
transparent risk scores.