Introduction
Composition of TME in B-cell lymphoma
Cell type | Common markers | Major role in tumors | Effects in B-cell lymphoma | References | |
---|---|---|---|---|---|
TAMs | M1 | CD68+ CD80+ CD86+ | Anti-tumorigenic | DLBCL: M2 TAMs correlate with poor prognosis HL: CD68+ TAMs correlate with poor prognosis FL: High CD68+ TAMs correlate with longer survival rates after R-CHOP | |
M2 | CD163+ CD204+ CD206+ | Pro-tumorigenic | |||
MDSCs | PMN-MDSCs | CD11b+ CD14− CD15+ CD66+ | Pro-tumorigenic | DLBCL: M-MDSCs correlate with poor prognosis HL: PMN-MDSCs correlate with poor prognosis FL: Unknown | |
M-MDSCs | Lin− CD11b+ CD14+ HLA-DRlow | ||||
TANs | N1 | CD16+ CD66b+ CD170low | Anti-tumorigenic | DLBCL: TANs correlate with poor prognosis HL: High neutrophil‐lymphocyte ratio correlates with poor prognosis in NS-cHL FL: Unknown | |
N2 | CD66b+ CD11b+ CD170high | Pro-tumorigenic | |||
NK cells | bone marrow NK cells | CD56bright CD16− | Anti-tumorigenic | DLBCL: Low NK cells correlate with shorter PFS HL: Unknown FL: Low peripheral blood NK cells count correlate with shorter PFS and OS | |
mature NK cells | CD56dim CD16+ | ||||
CAFs | α-SMA+ S100A4+ FAP+ CD10+ | Pro-tumorigenic | DLBCL: CAFs associate with favorable prognosis HL: CAFs protect Hodgkin and Reed–Sternberg cells from Brentuximab-Vedotin induced injury in NS-cHL FL: CAFs correlate with poor prognosis | ||
DCs | pDCs | CD123+ CD303+ CD304+ | Pro-tumorigenic | DLBCL: DCs correlate with longer survival HL: Unknown FL: Follicular DCs correlate with poor prognosis | |
mDCs | CD1c+ CD141+ |
TAMs
MDSCs
TANs
Tumor-infiltrating NK cells
CAFs
ECM
Other components of TME
Targeting the TME in B-cell lymphoma
Targeting components of the TME
TME cells | Target | Agent | Indication | Phase | Identifier |
---|---|---|---|---|---|
TAMs | SIRPα | TTI-622 | R/R lymphoma R/R multiple myeloma Newly diagnosed acute myeloid leukemia | I | NCT03530683 |
GS-0189 | R/R NHL | I | NCT04502706 | ||
CD47 | Hu5F9-G4 | R/R NHL | I | NCT02953509 | |
MDSCs | PI3Kδ/γ | Tenalisib (P65300) | iNHL | II | NCT03711578 |
TANs | SIRPα | IBI188 | Advanced lymphoma | I | NCT03717103 |
CD47/CD19 | TG-1801 | B-cell lymphoma | I | NCT03804996 | |
NK cells | iC9/CAR.19/IL15-transduced CB-NK Cells | B lymphoid malignancies NHL CLL ALL | I/II | NCT03056339 | |
CD19-targeted high-affinity NK | DLBCL | I | NCT04052061 | ||
AFM13 | R/R HL | I | NCT01221571 | ||
II | NCT02321592 | ||||
IL-15 | ALT-803 | R/R iNHL | I/II | NCT02384954 | |
CAFs | FGFR | JNJ-42756493 | Advanced or refractory lymphoma | I | NCT01962532 |
Targeting TAMs
Targeting MDSCs
Targeting TANs
NK cell-based immunotherapy
Targeting CAFs
Targeting the ECM
Targeting other TME cells
Targeting hypoxia, a hallmark of the TME
Immunotherapies for reversion of T cell exhaustion
PD-1/programmed cell death ligand 1 (PD-L1)
Identifier | B-cell lymphoma | Antibody, dose | Clinical significance | References |
---|---|---|---|---|
Anti-PD-1 monoclonal antibody | ||||
NCT02332668 | R/R HL (n = 15) | Pembrolizumab 2 mg/kg q3w | ORR 60%, CR 13%, PR 47% | [99] |
NCT03155425 | R/R cHL (n = 75) | Camrelizumab 200 mg q2w | ORR 76%, CR 28%, PR 48% | [100] |
NCT02961101 NCT03250962 | R/R cHL (n = 86) | Camrelizumab 200 mg q3w or Decitabine 10 mg/d, d1-5 + Camrelizumab 200 mg, d8 q3w | Camrelizumab (n = 19): CR 32% Decitabine + Camrelizumab (n = 42): CR 71% | [101] |
NCT03114683 | R/R cHL (n = 96) | Sintilimab 200 mg q3w | ORR 80.4%, CR 34%, PR 47% | [102] |
NCT03209973 | R/R cHL (n = 70) | Tislelizumab 200 mg q3w | ORR 87.1%, CR 62.9% 9 months: PFS 74.5% | [103] |
NCT01953692 | R/R PMBCL (n = 21) | Pembrolizumab 10 mg/kg q2w (n = 10) 200 mg q3w (n = 11) | ORR 48%, CR 33%, PR 14% | [104] |
NCT02332980 | R/R CLL (n = 16) RT DLBCL (n = 9) | Pembrolizumab 200 mg q3w | ORR 16% (CLL:0%, DLBCL:44%) CR (DLBCL) 11%, PR (DLBCL) 22% | [105] |
Anti-PD-L1 monoclonal antibody | ||||
NCT02401048 | R/R FL (n = 27) R/R DLBCL (n = 34) | Ibrutinib 560 mg qd + Durvalumab 10 mg/kg q2w | ORR (all patients) 25% ORR (FL) 26% ORR (GCB DLBCL) 13% ORR (non‐GCB DLBCL) 38% CR (FL) 4% CR (GCB DLBCL) 6% CR (non-GCB DLBCL) 31% median PFS 4.6 months median OS 18.1 months | [106] |
NCT02541604 | HL (n = 9) NHL (n = 3) | Atezolizumab 15 mg/kg (≤ 18 years) Atezolizumab 1200 mg (18-29 years) | PR (HL) 22.2% PR (NHL) 33.3% | [107] |
CTLA-4
Chimeric antigen receptor (CAR)-T cells
Cell product | Target | Cell dose | Indication | Clinical significance | Complications | References |
---|---|---|---|---|---|---|
Tisagenlecleucel (Kymriah) | CD19 | 0.1–6 × 108 | R/R DLBCL | ORR 52%, CR 40%, PR 12% | Cytopenias:32% Infections:20% NEs (grade 3 or worse):12%, CRS (grade 3 or worse):22% | [122] |
Axicabtagene ciloleucel (Yescarta) | CD19 | 2 × 106/kg | R/R large B-cell lymphoma | ORR 83%, CR 58% | Pyrexia:87% Anaemia:68% NEs (grade 3 or worse):32% CRS (grade 3 or worse):11% | [123] |
2 × 106/kg | R/R FL | ORR 95%, CR 80% | NEs (grade 3 or worse):19% CRS (grade 3 or worse):11% | [124] | ||
Brexucabtagene Autoleucel (Tecartus) | CD19 | 2 × 106/kg | R/R MCL | ORR 85%, CR 58% | Cytopenias:94% Infections:32% NEs (grade 3 or worse):31%, CRS (grade 3 or worse):15% | [125] |
Lisocabtagene maraleucel (Breyanzi) | CD19 | 50/100/150 × 106 | R/R large B-cell lymphoma | ORR 73%, CR 53% | Neutropenia:60% Anaemia:37% Thrombocytopenia:27% NEs (grade 3 or worse):10%, CRS (grade 3 or worse):2% | [126] |