Table 3 Drugs that modulate the expression of PD-L1 at tumor cell surface

Lenalidomide

Downregulates PD-L1

Currently used in clinical practice for the treatment of MM

Clinical trials: see Table 2 for trials combining lenalidomide to PD-1/PD-L1 inhibitors

[78]

Proteasome inhibitors

Upregulate PD-L1

Currently used in clinical practice

Clinical trials: see Table 2 for trials combining lenalidomide to PD-1/PD-L1 inhibitors

[34]

Oncolytic reovirus (Reolysin)

Upregulate PD-L1

Combined with lenalidomide or pomalidomide: phase 1 trial (NCT03015922)

Combined with bortezomib and dexamethasone: phase 1b trial (NCT02514382)

Combined with PD-L1 blockade: pre-clinical

[17, 90, 91]

HDAC inhibitors

Upregulate or downregulate PD-L1

Pan-HDAC inhibitor panobinostat: approved for RRMM

HDAC6 inhibitor combined with lenalidomide and dexamethasone: phase 1b (NCT0158328)

HDAC6 inhibitor combined with pomalidomide and dexamethasone: phase 1b (NCT02400242)

HDAC6 inhibitor and anti-PD-L1 antibody: pre-clinical

HDAC6 inhibitor with anti-PD-1 and lenalidomide: pre-clinical

Pan-HDAC inhibitor combined with Reolysin: pre-clinical

[23, 93, 95, 136]

MEK1/2 inhibitor

Blocks the expression of PD-L1 induced by IFN-γ;

U0126 can abrogate APRIL-induced expression of PD-L1 on MM cells

Pre-clinical (U0126)

Trametinib with dabrafenib: phase 1 (NCT03091257)

Trametinib with AKT inhibitor GSK2110183: phase 1 (NCT01476137)

Selumetinib: phase 2 (NCT01085214)

Binimetinib with encorafenib: phase 2 (NCT02834364)

Trametinib with GSK2141795: phase 2 (NCT01989598)

[14, 35, 99, 100]

Anti-APRIL monoclonal antibody hAPRIL01A

Downregulates PD-L1

Pre-clinical

[35, 97]

APRIL CAR T cells

Target BCMA and TACI

Phase 1/2 (NCT03287804)

Anti-BCMA

Downregulates PD-L1 (APRIL/BCMA signaling cascade)

Pre-clinical (GSK2857916)

GSK2857916: phase 1 (NCT02064387)

SEA-BCMA combined with ACTR087: phase 1 (NCT03266692)

JNJ-64007957: phase 1(NCT03145181)

PF-06863135: phase 1 (NCT03269136)

[96]

BCMA CAR T cells

Target BCMA

LCAR-B38M: clinical trial

bb2121: phase 1 (NCT02658929)

CART-BCMA: phase 1

CART- BCMA: phase 1 (NCT02215967)

[102,103,104,105]

BET inhibitors

Downregulate PD-L1

OTX015: phase 1 (NCT01713582)

Ongoing phase 1 clinical trials

(Pre-clinical in pancreatic and ovarian cancer, mouse model of lymphoma)

[106,107,108,109]

STAT3/BTK inhibition

Downregulates PD-L1

Ibrutinib and anti-PD-L1: pre-clinical

BBI608: phase 1 (NCT02352558)

Ibrutinib with carfilzomib: phase 1/2 (NCT01962792)

Ibrutinib, lenalidomide, and dexamethasone: phase 1/2 (NCT03015792)

Ibrutinib, pomalidomide, and dexamethasone: phase 1/2 (NCT02548962)

Ibrutinib, bortezomib, and dexamethasone: phase 2 (NCT02902965)

Ibrutinib (high-risk smoldering MM): phase 2 (NCT02943473)

(WP1066: pre-clinical in lymphoma;

Ibrutinib: pre-clinical in chronic lymphocytic leukemia)

[110,111,112]

MUC1-C inhibitors

Increase miR-34a and miR-200c, causing decreased expression of PD-L1

Tecemotide vaccine: phase 2

(NCT01094548)

ImMucin vaccine with hGM-CSF: phase 1/2 (NCT01232712)

(GO-203: pre-clinical in acute myeloid leukemia model, pre-clinical in lung cancer model)

[122, 123, 125]