Current Clinical Applications and Future Perspectives of Immune Checkpoint Inhibitors in Non-Hodgkin Lymphoma

Table 2

Synopsis of current evidence and evolving role of checkpoint inhibitors in selected subtypes of T-cell NHL.

Histologic subtype	Current level of evidence
	Alterations associated with an inflamed lymphoma environment	Clinical response to checkpoint inhibitors
PTCL, NOS	Weak; (i) A small subset of EBV-positive cases bears structural variations of PD-L1/PD-L2 [93].	Weak: studies with anti-PD-1 ICIs terminated due to cases with hyperprogression; (i) Disappointing ORR and DOR with anti-PD-1 ICIs in r/r disease [144, 145].; (ii) Hyperprogression in a third of cases; studies terminated.
ALCL	Moderate; (i) PD-L1 upregulation in ALK-positive and ALK-negative cases [134, 135].	Moderate to strong; (i) Data on a limited number of patients originating from small studies and case reports show impressive responses and durable CRs with anti-PD-1 ICI monotherapy in both ALK-positive and ALK-negative cases [145–149].; (ii) Ongoing clinical trial to determine efficacy in r/r setting and as consolidative therapy in patients achieving CR.
NKTCL	Moderate to strong; (i) Distinct molecular subtype with inflamed phenotype (PD-L1/PD-L2 SVs and JAK/STAT mutations) [136].; (ii) EBV-upregulated PD-L1 expression [37].	Strong; (i) High ORR and CR rates to anti-PD-1 ICIs in patients with r/r disease failing prior treatment with asparaginase [151–154].; (ii) Presence of mutated PD-L1 is a powerful predictive biomarker of response to anti-PD1 ICIs [155].; (iii) Ongoing clinical trials in upfront and r/r setting
ATLL	Moderate; (i) Aberrant PD-L1 expression in one-third of cases [138].; (ii) High mutational burden of TCR and NF-κB genes [139].	Studies with anti-PD-1 ICIs terminated due to hyperprogression; (i) Hyperprogression developed in first 3 patients after a single dose of anti-PD-1 ICI [156].; (ii) Hyperprogression implies that PD-1 functions as a tumor suppressor in ATLL and other T-cell malignancies [163].
MF and SS	Moderate; (i) PD-1 expression more pronounced in early stages and PD-L1 in more advanced stages of disease [140].; (ii) Genomic alterations of PD-1 and PD-L1 [141, 142].	Moderate; (i) Responses to pembrolizumab in over one-third of patients with r/r MF or r/r SS [159].; (ii) Cutaneous flare reaction common in patients with SS; no cases of hyperprogression.; (iii) Ongoing studies further assessing role of ICIs in cutaneous T-cell lymphomas.

Abbreviations: ALCL: anaplastic large cell lymphoma; ALK: anaplastic lymphoma kinase; ATLL: adult T-cell leukemia/lymphoma; CR: complete remission; DOR: duration of response; EBV: Epstein-Barr virus; ICI: immune checkpoint inhibitor; IGH: immunoglobulin heavy chain; JAK: Janus kinase; MCI: macrophage checkpoint inhibition; ME: microenvironment; MF: mycosis fungoides; NF-κΒ: nuclear factor kappa-light-chain-enhancer of activated B cells; NKTCL: natural killer T-cell lymphoma; ORR: overall response rate; PD-1: programmed cell-death protein 1; PD-L1: programmed cell-death 1 ligand 1; PTCL, NOS: peripheral T-cell lymphoma, not otherwise specified; r/r: relapsed/refractory; SS: Sézary syndrome; STAT: signal transducer and activator of transcription proteins; SVs: structural variations; TCR: T-cell receptor.