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Page 141 Hjalgrim et al. J Transl Genet Genom 2022;6:134-46 https://dx.doi.org/10.20517/jtgg.2021.46

One Achilles’ heel to the original protocol used to generate EBV-specific autologous T-cells in the study
[67]
[64]
reported by Bollard et al. and Heslop et al. was a rather lengthy production time - several months -
during which the patient’s disease may progress. The group therefore revised their protocol and succeeded
in generating autologous EBV-specific T-cells in a matter of weeks, that were seemingly equally effective in
a small trial of 24 patients with type II latency EBV-positive cHL or non-Hodgkin lymphomas [67,68] .

A further development in the use of EBV-specific T-cells has been trials using HLA-typed EBV-specific T-
cells from donors . So far, these trials have overwhelmingly concerned patients with post-transplant
[67]
[67]
lymphoproliferative disease . An extension of this idea is the ambition to develop off-the-shelf chimeric
antigen receptor cells by transducing EBV-specific T-cells of relevance in the treatment of both EBV-
positive and EBV-negative malignancies .
[69]

Whether or when EBV-specific T-cell therapy will eventually mature into a realistic treatment choice for
cHL remains to be seen. This may be in combination with other treatment modalities analogous to Burkitt
lymphoma, where a combination of hypomethylating agents inducing latency III programs in the malignant
cells and EBV-specific T-cells has been proposed .
[70]
[64]
Interestingly, Bollard et al. in their early study found that treatment response tended to be best for
patients who had received T-cells with LMP1 specific activity and for patients in whom apparent epitope
spreading to lymphoma antigens such as MAGE4, Survivin and PRAME was subsequently observed.

Recently, evidence to suggest that the presumed epitope spreading could be dependent on the induced
[71]
LMP1 expression in B-cells were reported by Choi et al. . Specifically, in a mouse model they
demonstrated that LMP1 signalling in B-cells induced expression and presentation of tumour associated
antigens on major histocompatibility complex classes I (MHC-I) and II (MHC-II) as well as upregulation of
costimulatory ligands inducing potent cytotoxic (CD4+ and CD8+) T cell responses .
[71]
In principle, this could indicate that treatment with cytotoxic T-cells stimulated with LMP1 might also be
[72]
effective in EBV-negative cHL, which do also express lymphoma antigens . Indeed, in an additional
experiment Choi et al. showed that stimulation of autologous CD4 cells by CLL cells with induced LMP-1
[71]
expression produced cytotoxic T-cells capable of lysing CLL cells in vitro.

Besides suppression of HLA expression, one of the numerous mechanisms by which cHL HRS cells evade
host immune response, is by expressing PD-L1/L2. This allows the HRS cells to interact with tumour-
specific cytotoxic T-cells in the TME expressing the PD1, thereby effectively abrogating the T-cells’
activity .
[5]

The HRS cells’ overexpression of PD-L1 and PD-L2 is achieved by several different mechanisms including
especially alterations of the 9p24.1 locus, which are seen in both EBV-negative and EBV-positive cHL [5,58,72] .

However, for two reasons PD-L1 expression may be more pronounced in EBV-positive cHL than in EBV-
negative cases. First, in EBV-positive, activation of the PA1 and JAK/STAT signalling pathway by LMP1
may increase PD-L1 expression [5,58] . Secondly, PD-L1 is also expressed by tumour-associated macrophages
[73]
(TAM), which are more abundant in EBV-positive than in EBV-negative cHL TME , co-localise with
PD-L1 positive HRS cells and frequency of which have been associated with prognosis . For TAM, the
[74]
[58]
[75]
immune suppressing effect may even be expanded to PD-1 expressing natural killer cells in the TME .